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Timothy Arthur James Haystead

Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
Duke Box 3813, Durham, NC 27710
C 118 LSRC, Durham, NC 27708

Selected Publications


Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.

Journal Article Cell Chem Biol · April 18, 2024 The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp9 ... Full text Link to item Cite

TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers.

Journal Article Cell Death Dis · April 17, 2024 Poor survival and lack of treatment response in glioblastoma (GBM) is attributed to the persistence of glioma stem cells (GSCs). To identify novel therapeutic approaches, we performed CRISPR/Cas9 knockout screens and discovered TGFβ activated kinase (TAK1) ... Full text Link to item Cite

Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.

Journal Article Cell Chem Biol · March 21, 2024 Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver ... Full text Link to item Cite

Investigation of SARS-CoV-2 individual proteins reveals the in vitro and in vivo immunogenicity of membrane protein.

Journal Article Sci Rep · December 18, 2023 Evidence in SARS-CoV-2 patients have identified that viral infection is accompanied by the expression of inflammatory mediators by both immune and stromal cells within the pulmonary system. However, the immunogenicity of individual SARS-CoV-2 proteins has ... Full text Link to item Cite

Transforming Growth Factor-β-Activated Kinase 1 (TAK1) Mediates Chronic Pain and Cytokine Production in Mouse Models of Inflammatory, Neuropathic, and Primary Pain.

Journal Article The journal of pain · September 2023 The origin of chronic pain is linked to inflammation, characterized by increased levels of proinflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of proinflammatory ... Full text Open Access Cite

Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis.

Journal Article Pharmacol Res Perspect · August 2023 Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor ... Full text Link to item Cite

Pharmacological inhibition of TAK1 prevents and induces regression of experimental organ fibrosis.

Journal Article JCI Insight · July 24, 2023 Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-β and TLR signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to ... Full text Link to item Cite

Death-associated protein kinase 3 regulates the myogenic reactivity of cerebral arteries.

Journal Article Exp Physiol · July 2023 NEW FINDINGS: What is the central question of this study? DAPK3 contributes to the Ca2+ -sensitization of vascular smooth muscle contraction: does this protein kinase participate in the myogenic response of cerebral arteries? What is the main finding and i ... Full text Link to item Cite

A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity.

Journal Article Cancers (Basel) · November 23, 2022 Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high he ... Full text Link to item Cite

Expression of membrane Hsp90 is a molecular signature of T cell activation.

Journal Article Sci Rep · October 27, 2022 Heat shock protein 90 (Hsp90) maintains cellular proteostasis during stress and has been under investigation as a therapeutic target in cancer for over two decades. We and others have identified a membrane expressed form of Hsp90 (mHsp90) that previously a ... Full text Link to item Cite

Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers.

Journal Article J Immunother Cancer · September 2022 BACKGROUND: We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induc ... Full text Link to item Cite

Mechanisms by which smoothelin-like protein 1 reverses insulin resistance in myotubules and mice.

Journal Article Mol Cell Endocrinol · July 1, 2022 Insulin resistance (InR) is manifested in skeletal muscle by decreased insulin-stimulated glucose uptake due to impaired insulin signaling and multiple post-receptor intracellular defects. Chronic glucose-induced insulin resistance leads to the activation ... Full text Link to item Cite

Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.

Journal Article Pain · June 1, 2022 Heat shock protein 90 (Hsp90) is a ubiquitously expressed integral cellular protein essential for regulating proteomic stress. Previous research has shown that Hsp90 regulates critical signaling pathways underlying chronic pain and inflammation. Recent dis ... Full text Open Access Link to item Cite

Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis.

Journal Article ACS Chem Biol · March 18, 2022 Selective targeting of TNF in inflammatory diseases such as rheumatoid arthritis (RA) has provided great therapeutic benefit to many patients with chronic RA. Although these therapies show initially high response rates, their therapeutic benefit is limited ... Full text Link to item Cite

HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.

Journal Article Mol Cancer Ther · January 2022 A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of n ... Full text Link to item Cite

Oral Hsp90 inhibitor SNX-5422 attenuates SARS-CoV-2 replication and dampens inflammation in airway cells.

Journal Article iScience · December 17, 2021 Currently available SARS-CoV-2 therapeutics are targeted toward moderately to severely ill patients and require intravenous infusions, with limited options for exposed or infected patients with no or mild symptoms. Although vaccines have demonstrated prote ... Full text Link to item Cite

A bioorthogonal chemical reporter for fatty acid synthase-dependent protein acylation.

Journal Article J Biol Chem · November 2021 Mammalian cells acquire fatty acids (FAs) from dietary sources or via de novo palmitate production by fatty acid synthase (FASN). Although most cells express FASN at low levels, it is upregulated in cancers of the breast, prostate, and liver, among others, ... Full text Link to item Cite

The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.

Journal Article Nat Struct Mol Biol · August 2021 Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regul ... Full text Link to item Cite

Understanding the sources of errors in ex vivo Hsp90 molecular imaging for rapid-on-site breast cancer diagnosis.

Journal Article Biomed Opt Express · April 1, 2021 Overexpression of heat shock protein 90 (Hsp90) on the surface of breast cancer cells makes it an attractive molecular biomarker for breast cancer diagnosis. Before a ubiquitous diagnostic method can be established, an understanding of the systematic error ... Full text Link to item Cite

Transcription factor-driven alternative localization of Cryptococcus neoformans superoxide dismutase.

Journal Article J Biol Chem · 2021 Cryptococcus neoformans is an opportunistic fungal pathogen whose pathogenic lifestyle is linked to its ability to cope with fluctuating levels of copper (Cu), an essential metal involved in multiple virulence mechanisms, within distinct host niches. Durin ... Full text Link to item Cite

Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.

Journal Article Cell Chem Biol · April 18, 2024 The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp9 ... Full text Link to item Cite

TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers.

Journal Article Cell Death Dis · April 17, 2024 Poor survival and lack of treatment response in glioblastoma (GBM) is attributed to the persistence of glioma stem cells (GSCs). To identify novel therapeutic approaches, we performed CRISPR/Cas9 knockout screens and discovered TGFβ activated kinase (TAK1) ... Full text Link to item Cite

Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.

Journal Article Cell Chem Biol · March 21, 2024 Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver ... Full text Link to item Cite

Investigation of SARS-CoV-2 individual proteins reveals the in vitro and in vivo immunogenicity of membrane protein.

Journal Article Sci Rep · December 18, 2023 Evidence in SARS-CoV-2 patients have identified that viral infection is accompanied by the expression of inflammatory mediators by both immune and stromal cells within the pulmonary system. However, the immunogenicity of individual SARS-CoV-2 proteins has ... Full text Link to item Cite

Transforming Growth Factor-β-Activated Kinase 1 (TAK1) Mediates Chronic Pain and Cytokine Production in Mouse Models of Inflammatory, Neuropathic, and Primary Pain.

Journal Article The journal of pain · September 2023 The origin of chronic pain is linked to inflammation, characterized by increased levels of proinflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of proinflammatory ... Full text Open Access Cite

Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis.

Journal Article Pharmacol Res Perspect · August 2023 Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor ... Full text Link to item Cite

Pharmacological inhibition of TAK1 prevents and induces regression of experimental organ fibrosis.

Journal Article JCI Insight · July 24, 2023 Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-β and TLR signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to ... Full text Link to item Cite

Death-associated protein kinase 3 regulates the myogenic reactivity of cerebral arteries.

Journal Article Exp Physiol · July 2023 NEW FINDINGS: What is the central question of this study? DAPK3 contributes to the Ca2+ -sensitization of vascular smooth muscle contraction: does this protein kinase participate in the myogenic response of cerebral arteries? What is the main finding and i ... Full text Link to item Cite

A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity.

Journal Article Cancers (Basel) · November 23, 2022 Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high he ... Full text Link to item Cite

Expression of membrane Hsp90 is a molecular signature of T cell activation.

Journal Article Sci Rep · October 27, 2022 Heat shock protein 90 (Hsp90) maintains cellular proteostasis during stress and has been under investigation as a therapeutic target in cancer for over two decades. We and others have identified a membrane expressed form of Hsp90 (mHsp90) that previously a ... Full text Link to item Cite

Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers.

Journal Article J Immunother Cancer · September 2022 BACKGROUND: We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induc ... Full text Link to item Cite

Mechanisms by which smoothelin-like protein 1 reverses insulin resistance in myotubules and mice.

Journal Article Mol Cell Endocrinol · July 1, 2022 Insulin resistance (InR) is manifested in skeletal muscle by decreased insulin-stimulated glucose uptake due to impaired insulin signaling and multiple post-receptor intracellular defects. Chronic glucose-induced insulin resistance leads to the activation ... Full text Link to item Cite

Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.

Journal Article Pain · June 1, 2022 Heat shock protein 90 (Hsp90) is a ubiquitously expressed integral cellular protein essential for regulating proteomic stress. Previous research has shown that Hsp90 regulates critical signaling pathways underlying chronic pain and inflammation. Recent dis ... Full text Open Access Link to item Cite

Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis.

Journal Article ACS Chem Biol · March 18, 2022 Selective targeting of TNF in inflammatory diseases such as rheumatoid arthritis (RA) has provided great therapeutic benefit to many patients with chronic RA. Although these therapies show initially high response rates, their therapeutic benefit is limited ... Full text Link to item Cite

HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.

Journal Article Mol Cancer Ther · January 2022 A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of n ... Full text Link to item Cite

Oral Hsp90 inhibitor SNX-5422 attenuates SARS-CoV-2 replication and dampens inflammation in airway cells.

Journal Article iScience · December 17, 2021 Currently available SARS-CoV-2 therapeutics are targeted toward moderately to severely ill patients and require intravenous infusions, with limited options for exposed or infected patients with no or mild symptoms. Although vaccines have demonstrated prote ... Full text Link to item Cite

A bioorthogonal chemical reporter for fatty acid synthase-dependent protein acylation.

Journal Article J Biol Chem · November 2021 Mammalian cells acquire fatty acids (FAs) from dietary sources or via de novo palmitate production by fatty acid synthase (FASN). Although most cells express FASN at low levels, it is upregulated in cancers of the breast, prostate, and liver, among others, ... Full text Link to item Cite

The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.

Journal Article Nat Struct Mol Biol · August 2021 Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regul ... Full text Link to item Cite

Understanding the sources of errors in ex vivo Hsp90 molecular imaging for rapid-on-site breast cancer diagnosis.

Journal Article Biomed Opt Express · April 1, 2021 Overexpression of heat shock protein 90 (Hsp90) on the surface of breast cancer cells makes it an attractive molecular biomarker for breast cancer diagnosis. Before a ubiquitous diagnostic method can be established, an understanding of the systematic error ... Full text Link to item Cite

Transcription factor-driven alternative localization of Cryptococcus neoformans superoxide dismutase.

Journal Article J Biol Chem · 2021 Cryptococcus neoformans is an opportunistic fungal pathogen whose pathogenic lifestyle is linked to its ability to cope with fluctuating levels of copper (Cu), an essential metal involved in multiple virulence mechanisms, within distinct host niches. Durin ... Full text Link to item Cite

Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.

Journal Article Sci Transl Med · December 16, 2020 Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy r ... Full text Link to item Cite

TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases.

Journal Article Open Biol · September 2020 Aberrant tumour necrosis factor (TNF) signalling is a hallmark of many inflammatory diseases including rheumatoid arthritis (RA), irritable bowel disease and lupus. Maladaptive TNF signalling can lead to hyper active downstream nuclear factor (NF)-κβ signa ... Full text Link to item Cite

TAK1 regulates the tumor microenvironment through inflammatory, angiogenetic and apoptotic signaling cascades.

Journal Article Oncotarget · May 26, 2020 Transforming growth factor beta-activated kinase 1 (TAK1) has been implicated for its role in inflammatory signaling and as an important mediator of cellular apoptosis and necroptosis in various cell types. Our recent discovery of a first-in-class, potent ... Full text Link to item Cite

Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.

Journal Article Commun Biol · May 8, 2020 Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a ... Full text Link to item Cite

A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase.

Journal Article J Biol Chem · February 7, 2020 Interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-4, as well as transforming growth factor β-activated kinase 1 (TAK1), are protein kinases essential for transducing inflammatory signals from interleukin receptors. IRAK family proteins and TAK1 ... Full text Link to item Cite

Leveraging surface Hsp90 expression for rapid-on-site breast cancer diagnostics

Conference Optics InfoBase Conference Papers · January 1, 2020 We developed a portable, low-cost, handheld fluorescent microscope to perform rapid heat shock protein 90 (Hsp90) molecular imaging. The source of non-specific signal and diffusion kinetics of the probe is studied. ... Cite

Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice.

Journal Article Arthritis Res Ther · December 17, 2019 OBJECTIVES: To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. METHODS: Fo ... Full text Link to item Cite

Application of immobilized ATP to the study of NLRP inflammasomes.

Journal Article Arch Biochem Biophys · July 30, 2019 The NLRP proteins are a subfamily of the NOD-like receptor (NLR) innate immune sensors that possess an ATP-binding NACHT domain. As the most well studied member, NLRP3 can initiate the assembly process of a multiprotein complex, termed the inflammasome, up ... Full text Link to item Cite

Copine A Interacts with Actin Filaments and Plays a Role in Chemotaxis and Adhesion.

Journal Article Cells · July 21, 2019 Copines make up a family of calcium-dependent, phospholipid-binding proteins found in numerous eukaryotic organisms. Copine proteins consist of two C2 domains at the N-terminus followed by an A domain similar to the von Willebrand A domain found in integri ... Full text Link to item Cite

Plasmodium PK9 Inhibitors Promote Growth of Liver-Stage Parasites.

Journal Article Cell Chem Biol · March 21, 2019 There is a scarcity of pharmacological tools to interrogate protein kinase function in Plasmodium parasites, the causative agent of malaria. Among Plasmodium's protein kinases, those characterized as atypical represent attractive drug targets as they lack ... Full text Link to item Cite

Exploiting heat shock protein expression to develop a non-invasive diagnostic tool for breast cancer.

Journal Article Sci Rep · March 5, 2019 Leveraging the unique surface expression of heat shock protein 90 (Hsp90) in breast cancer provides an exciting opportunity to develop rapid diagnostic tests at the point-of-care setting. Hsp90 has previously been shown to have elevated expression levels a ... Full text Link to item Cite

Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90.

Journal Article Cell Rep · January 29, 2019 The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs ab ... Full text Link to item Cite

Smoothelin-like 1 deletion enhances myogenic reactivity of mesenteric arteries with alterations in PKC and myosin phosphatase signaling.

Journal Article Sci Rep · January 24, 2019 The role of the smoothelin-like 1 (SMTNL1) protein in mediating vascular smooth muscle contractile responses to intraluminal pressure was examined in resistance vessels. Mesenteric arterioles from wild type (WT) and SMTNL1 global knock-out (KO) mice were e ... Full text Link to item Cite

Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion.

Journal Article Sci Rep · November 19, 2018 Immune challenge of invading macrophages at sites of infection is associated with release of TNF, which triggers a local cytokine storm as part of the normal inflammatory response. Whereas this response maybe beneficial in fighting off infections, similar ... Full text Link to item Cite

Targeting Pim Kinases and DAPK3 to Control Hypertension.

Journal Article Cell Chem Biol · October 18, 2018 Sustained vascular smooth muscle hypercontractility promotes hypertension and cardiovascular disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that ... Full text Link to item Cite

Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development.

Journal Article Cell Stress Chaperones · July 2018 The molecular chaperone Hsp90 is one component of a highly complex and interactive cellular proteostasis network (PN) that participates in protein folding, directs misfolded and damaged proteins for destruction, and participates in regulating cellular tran ... Full text Link to item Cite

Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

Journal Article Antimicrob Agents Chemother · April 2018 Malaria remains a global health burden partly due to Plasmodium parasite resistance to first-line therapeutics. The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an essential protein for blood-stage Plasmodium parasites, but details abou ... Full text Link to item Cite

Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis.

Journal Article Eur Respir J · February 2018 Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major sour ... Full text Link to item Cite

Fluorescent-Linked Enzyme Chemoproteomic Strategy (FLECS) for Identifying HSP70 Inhibitors.

Journal Article Methods Mol Biol · 2018 Activation of the heat shock response, and in particular upregulation of stress-inducible Hsp70, herein referred to as Hsp70i, in newly transformed cells, appears to protect against protein damaging stimuli, induction of premature oncogene-induced terminal ... Full text Link to item Cite

Optimizing fluorescently-tethered Hsp90 inhibitor dose for maximal specific uptake by breast tumors

Conference Progress in Biomedical Optics and Imaging - Proceedings of SPIE · January 1, 2018 Despite improvements in surgical resection, 20-40% of patients undergoing breast conserving surgery require at least one additional re-excision. Leveraging the unique surface expression of heat shock protein 90 (Hsp90), a chaperone protein involved in seve ... Full text Cite

In Vivo Detection of HSP90 Identifies Breast Cancers with Aggressive Behavior.

Journal Article Clin Cancer Res · December 15, 2017 Purpose: Hsp90, a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers. We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive breast ... Full text Link to item Cite

Leveraging ectopic Hsp90 expression to assay the presence of tumor cells and aggressive tumor phenotypes in breast specimens.

Journal Article Sci Rep · December 13, 2017 Hsp90 has been studied extensively as a therapeutic target in breast cancer in pre-clinical and clinical trials, demonstrating a variety of roles in metastatic progression. The evidence to date suggests a compelling opportunity to leverage attributes of Hs ... Full text Link to item Cite

Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer.

Journal Article Cell Rep · November 14, 2017 The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90), promote the activation of PP5. However, it is unclear whether post-translational modific ... Full text Link to item Cite

Near-simultaneous intravital microscopy of glucose uptake and mitochondrial membrane potential, key endpoints that reflect major metabolic axes in cancer.

Journal Article Sci Rep · October 23, 2017 While the demand for metabolic imaging has increased in recent years, simultaneous in vivo measurement of multiple metabolic endpoints remains challenging. Here we report on a novel technique that provides in vivo high-resolution simultaneous imaging of gl ... Full text Link to item Cite

Cellular fatty acid synthase is required for late stages of HIV-1 replication.

Journal Article Retrovirology · September 29, 2017 BACKGROUND: Like all viruses, HIV-1 relies on host systems to replicate. The human purinome consists of approximately two thousand proteins that bind and use purines such as ATP, NADH, and NADPH. By virtue of their purine binding pockets, purinome proteins ... Full text Link to item Cite

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease.

Journal Article Cell Chem Biol · August 17, 2017 Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-T ... Full text Link to item Cite

A Fluorescent Hsp90 Probe Demonstrates the Unique Association between Extracellular Hsp90 and Malignancy in Vivo.

Journal Article ACS Chem Biol · April 21, 2017 Extracellular expression of heat shock protein 90 (eHsp90) by tumor cells is correlated with malignancy. Development of small molecule probes that can detect eHsp90 in vivo may therefore have utility in the early detection of malignancy. We synthesized a c ... Full text Link to item Cite

Immunogenic cancer cell death selectively induced by near infrared photoimmunotherapy initiates host tumor immunity.

Journal Article Oncotarget · February 7, 2017 Immunogenic cell death (ICD) is a form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Cancer cells killed via ICD can elicit antitumor immunity. ICD is efficiently induced by near-infrared photo-immunotherap ... Full text Link to item Cite

Hsp90: A key target in HIV infection

Journal Article Future Virology · February 1, 2017 Full text Cite

Cryo-sectioned mice for investigating HS-131 uptake

Dataset · July 18, 2016 Data related to submitted manuscript “A far-red Hsp90 inhibitor reveals mechanism underlying external Hsp90 trafficking”. Brightfield and fluorescence images of an experimental mouse (721 images each) and control mouse (620 images each). ... Full text Cite

Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules.

Journal Article ACS Chem Biol · July 15, 2016 Three scaffolds with inhibitory activity against the heat shock protein 70 (Hsp70) family of chaperones have been found to enhance the degradation of the microtubule associated protein tau in cells, neurons, and brain tissue. This is important because tau ... Full text Link to item Cite

The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.

Journal Article Nat Commun · June 29, 2016 Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it ... Full text Link to item Cite

Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer.

Journal Article Cell Chem Biol · June 23, 2016 Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive re ... Full text Link to item Cite

An inducible heat shock protein 70 small molecule inhibitor demonstrates anti-dengue virus activity, validating Hsp70 as a host antiviral target.

Journal Article Antiviral Res · June 2016 An estimated three billion people are at risk of Dengue virus (DENV) infection worldwide and there are currently no approved therapeutic interventions for DENV infection. Due to the relatively small size of the DENV genome, DENV is reliant on host factors ... Full text Link to item Cite

A Small Molecule Pyrazolo[3,4-d]Pyrimidinone Inhibitor of Zipper-Interacting Protein Kinase Suppresses Calcium Sensitization of Vascular Smooth Muscle.

Journal Article Mol Pharmacol · January 2016 A novel inhibitor of zipper-interacting protein kinase (ZIPK) was used to examine the involvement of ZIPK in the regulation of smooth muscle contraction. Pretreatment of de-endothelialized rat caudal arterial smooth muscle strips with the pyrazolo[3,4-d]py ... Full text Link to item Cite

c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells.

Journal Article Cell Rep · August 11, 2015 The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mecha ... Full text Link to item Cite

Pregnancy and Smoothelin-like Protein 1 (SMTNL1) Deletion Promote the Switching of Skeletal Muscle to a Glycolytic Phenotype in Human and Mice.

Journal Article J Biol Chem · July 17, 2015 Pregnancy promotes physiological adaptations throughout the body, mediated by the female sex hormones progesterone and estrogen. Changes in the metabolic properties of skeletal muscle enable the female body to cope with the physiological challenges of preg ... Full text Link to item Cite

Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70.

Journal Article Chem Biol · December 18, 2014 Inducible Hsp70 (Hsp70i) is overexpressed in a wide spectrum of human tumors, and its expression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Identification of small-molecule inhibitors selective for Hsp70i could p ... Full text Link to item Cite

Chikungunya virus nsP3 & nsP4 interacts with HSP-90 to promote virus replication: HSP-90 inhibitors reduce CHIKV infection and inflammation in vivo.

Journal Article Antiviral Res · March 2014 The global emergence of Chikungunya virus (CHIKV) infection is alarming and currently there is no licensed vaccine or antiviral treatment available to mitigate this disease. CHIKV infection typically results in high viral load with an outcome of high fever ... Full text Link to item Cite

Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor.

Journal Article ACS Chem Biol · December 20, 2013 DAPK1 and ZIPK (also called DAPK3) are closely related serine/threonine protein kinases that regulate programmed cell death and phosphorylation of non-muscle and smooth muscle myosin. We have developed a fluorescence linked enzyme chemoproteomic strategy ( ... Full text Link to item Cite

The RNA-binding protein Fus directs translation of localized mrnas in APC-RNP granules

Journal Article Journal of Cell Biology · December 9, 2013 RNA localization pathways direct numerous mRNAs to distinct subcellular regions and affect many physiological processes. In one such pathway the tumor-suppressor protein adenomatous polyposis coli (APC) targets RNAs to cell protrusions, forming APCcontaini ... Full text Cite

Abstract C86: Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

Conference Molecular Cancer Therapeutics · November 1, 2013 AbstractHsp90 inhibitors have demonstrated unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained but could be influenced by ectopically expressed Hsp ... Full text Cite

Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

Journal Article Chem Biol · September 19, 2013 Inhibitors of heat-shock protein 90 (Hsp90) have demonstrated an unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained, but could be influenced by ectopically expressed Hsp90 in tumors. In this work ... Full text Link to item Cite

Hsp90, an unlikely ally in the war on cancer.

Journal Article FEBS J · March 2013 On the surface heat shock protein 90 (Hsp90) is an unlikely drug target for the treatment of any disease, let alone cancer. Hsp90 is highly conserved and ubiquitously expressed in all cells. There are two major isoforms α and β encoded by distinct genes an ... Full text Link to item Cite

Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance.

Journal Article Cell Host Microbe · August 16, 2012 Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains ... Full text Link to item Cite

A highly selective Hsp90 affinity chromatography resin with a cleavable linker.

Journal Article Bioorg Med Chem · May 15, 2012 Over 200 proteins have been identified that interact with the protein chaperone Hsp90, a recognized therapeutic target thought to participate in non-oncogene addiction in a variety of human cancers. However, defining Hsp90 clients is challenging because in ... Full text Link to item Cite

Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer.

Journal Article Breast Cancer Res · April 17, 2012 INTRODUCTION: Although human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapi ... Full text Link to item Cite

Chemoproteomic characterization of protein kinase inhibitors using immobilized ATP.

Journal Article Methods Mol Biol · 2012 Protein kinase inhibitors have emerged as indispensable tools for the elucidation of the biological functions of specific signal transduction pathways and as promising candidates for molecular-targeted therapy. However, because many protein kinase inhibito ... Full text Link to item Cite

Smoothelin-like 1 protein is a bifunctional regulator of the progesterone receptor during pregnancy.

Journal Article J Biol Chem · September 9, 2011 During pregnancy, uterine smooth muscle (USM) coordinately adapts its contractile phenotype in order to accommodate the developing fetus and then prepare for delivery. Herein we show that SMTNL1 plays a major role in pregnancy to promote adaptive responses ... Full text Link to item Cite

Efficient detection of RNA-protein interactions using tethered RNAs.

Journal Article Nucleic Acids Res · April 2011 The diverse localization of transcripts in cells suggests that there are many specific RNA-protein interactions that have yet to be identified. Progress has been limited, however, by the lack of a robust method to detect and isolate the RNA-binding protein ... Full text Link to item Cite

Angiotensin II type 1A receptors in vascular smooth muscle cells do not influence aortic remodeling in hypertension.

Journal Article Hypertension · March 2011 Vascular injury and remodeling are common pathological sequelae of hypertension. Previous studies have suggested that the renin-angiotensin system acting through the type 1 angiotensin II (AT(1)) receptor promotes vascular pathology in hypertension. To stu ... Full text Link to item Cite

Phosphorylation-dependent control of ZIPK nuclear import is species specific.

Journal Article Cell Signal · January 2011 ZIPK (zipper-interacting protein kinase) is a Ca(2+)-independent protein kinase that promotes myosin phosphorylation in both smooth muscle and non-muscle cells. A recent report attempted to clarify a debate over the subcellular localization of ZIPK in non- ... Full text Link to item Cite

Smoothelin-like 1 protein regulates myosin phosphatase-targeting subunit 1 expression during sexual development and pregnancy.

Journal Article J Biol Chem · September 17, 2010 Pregnancy coordinately alters the contractile properties of both vascular and uterine smooth muscles reducing systemic blood pressure and maintaining uterine relaxation. The precise molecular mechanisms underlying these pregnancy-induced adaptations have y ... Full text Link to item Cite

Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90.

Journal Article Chem Biol · July 30, 2010 A chemoproteomics-based drug discovery strategy is presented that utilizes a highly parallel screening platform, encompassing more than 1000 targets, with a focused chemical library prior to target selection. This chemoproteomics-based process enables a da ... Full text Link to item Cite

The role of the calponin homology domain of smoothelin-like 1 (SMTNL1) in myosin phosphatase inhibition and smooth muscle contraction.

Journal Article Mol Cell Biochem · July 2009 In this study, we provide further insight into the contribution of the smoothelin-like 1 (SMTNL1) calponin homology (CH)-domain on myosin light chain phosphatase (SMPP-1M) activity and smooth muscle contraction. SMTNL1 protein was shown to have inhibitory ... Full text Link to item Cite

Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor.

Journal Article J Biol Chem · June 19, 2009 Epidermal growth factor receptor (EGFR) gene amplification, mutations, and/or aberrant activation are frequent abnormalities in malignant gliomas and other human cancers and have been associated with an aggressive clinical course and a poor therapeutic out ... Full text Link to item Cite

Rapid Characterization of in vivo Phosphorylation Sites and the Protein Kinases and Phosphatases that Regulate them by Affinity Capture

Journal Article · January 1, 2009 This chapter discusses methodologies for analysis of the phosphoproteome, and describes how affinity captures using naturally occurring small molecules can be utilized to define protein kinases and phosphatases regulating phosphorylation events in vivo. In ... Full text Cite

Protein kinases of malaria parasites: an update.

Journal Article Trends Parasitol · December 2008 Protein kinases (PKs) play crucial roles in the control of proliferation and differentiation in eukaryotic cells. Research on protein phosphorylation has expanded tremendously in the past few years, in part as a consequence of the realization that PKs repr ... Full text Link to item Cite

An unbiased evaluation of CK2 inhibitors by chemoproteomics: characterization of inhibitor effects on CK2 and identification of novel inhibitor targets.

Journal Article Mol Cell Proteomics · June 2008 Recently protein kinases have emerged as some of the most promising drug targets; and therefore, pharmaceutical strategies have been developed to inhibit kinases in the treatment of a variety of diseases. CK2 is a serine/threonine-protein kinase that has b ... Full text Link to item Cite

Human cytidine triphosphate synthetase 1 interacting proteins.

Journal Article Nucleosides Nucleotides Nucleic Acids · June 2008 We investigated the interacting proteins and intracellular localization of CTP synthetase 1 (CTPS1) in mammalian cells. CTPS1 interacted with a GST- peptidyl prolyl isomerase, Pin1 fusion (GST-Pin1) in a Ser 575 (S575) phosphorylation-dependent manner. Imm ... Full text Link to item Cite

Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle.

Journal Article J Biol Chem · April 25, 2008 Featured Publication In vivo protein kinases A and G (PKA and PKG) coordinately phosphorylate a broad range of substrates to mediate their various physiological effects. The functions of many of these substrates have yet to be defined genetically. Herein we show a role for smo ... Full text Link to item Cite

Murine CD7 shares antigenic cross-reactivity with HSP-60.

Journal Article Hybridoma (Larchmt) · April 2008 Human (h) CD7 is a 40 kDa single chain Ig superfamily molecule that is expressed on thymocytes, a major subunit of peripheral T cells, and most natural killer cells. Ligands for hCD7 include the epithelial cell-produced molecule, K-12, and galectin. Mice d ... Full text Link to item Cite

Proteomic identification of the cerebral cavernous malformation signaling complex.

Journal Article J Proteome Res · November 2007 Cerebral cavernous malformations (CCM) are sporadic or inherited vascular lesions of the central nervous system characterized by dilated, thin-walled, leaky vessels. Linkage studies have mapped autosomal dominant mutations to three loci: ccm1 (KRIT1), ccm2 ... Full text Link to item Cite

Characterization of a UBC13 kinase in Plasmodium falciparum.

Journal Article Proc Natl Acad Sci U S A · May 8, 2007 Featured Publication Protein kinases are generally recognized as attractive drug targets to treat a variety of human diseases. Recent analysis of the Plasmodium falciparum kinome identified several kinases that are entirely unique to Plasmodium species. The specific functions ... Full text Link to item Cite

A conserved family of enzymes that phosphorylate inositol hexakisphosphate.

Journal Article Science · April 6, 2007 Inositol pyrophosphates are a diverse group of high-energy signaling molecules whose cellular roles remain an active area of study. We report a previously uncharacterized class of inositol pyrophosphate synthase and find it is identical to yeast Vip1 and A ... Full text Link to item Cite

Dual kinase-mediated regulation of PITK by CaMKII and GSK3.

Journal Article Cell Signal · March 2007 Featured Publication Phosphatase Interactor Targeting K protein (PITK) was previously identified as a novel PP1 targeting subunit implicated in modulating the phosphorylation of the transcriptional regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K) [Kwiek NC, Thacke ... Full text Link to item Cite

ROCK1 phosphorylates and activates zipper-interacting protein kinase.

Journal Article J Biol Chem · February 16, 2007 Featured Publication Zipper-interacting protein kinase (ZIPK) regulates Ca(2+)-independent phosphorylation of both smooth muscle (to regulate contraction) and non-muscle myosin (to regulate non-apoptotic cell death) through either phosphorylation and inhibition of myosin phosp ... Full text Link to item Cite

Clostridium taeniosporum spore ribbon-like appendage structure, composition and genes.

Journal Article Mol Microbiol · February 2007 Clostridium taeniosporum spores have about 12 large, flat, ribbon-like appendages attached through a common trunk at one spore pole to a previously unknown surface layer outside the coat that is proposed to be called the 'encasement'. Appendages are about ... Full text Link to item Cite

Staurosporine inhibition of zipper-interacting protein kinase contractile effects in gastrointestinal smooth muscle.

Journal Article Biochem Cell Biol · February 2007 Zipper-interacting protein kinase (ZIPK) is a serine-threonine kinase that has been implicated in Ca2+-independent myosin II phosphorylation and contractile force generation in vascular smooth muscle. However, relatively little is known about the contribut ... Full text Link to item Cite

Synthesis and use of the protein phosphatase affinity matrices microcystin-sepharose and microcystin-biotin-sepharose.

Journal Article Methods Mol Biol · 2007 Microcystin-based affinity matrices have been utilized to demonstrate the association of signaling proteins with protein phosphatases and for the purification of low-abundance microcystin-sensitive protein phosphatases. Here, we describe the procedure for ... Full text Link to item Cite

Real-time in vivo proteomic identification of novel kinase substrates in smooth muscle.

Journal Article Methods Mol Biol · 2007 Featured Publication Relaxation of smooth muscle can occur through agonists (such as nitric oxide) that activate guanylyl cyclase and stimulate the production of cGMP, activating its target, cGMP-dependent protein kinase (PKG). This kinase can raise the Ca2+ threshold for cont ... Full text Link to item Cite

Affinity Purification with Natural Immobilized Ligands

Journal Article · December 1, 2006 This chapter discusses affinity chromatography-based techniques to examine protein interaction between other proteins or small ligands. The first procedure involves the use of toxin microcystin LR (MC-LR) conjugated to a biotin or Sepharose matrix to bioch ... Full text Cite

PITK, a PP1 targeting subunit that modulates the phosphorylation of the transcriptional regulator hnRNP K.

Journal Article Cell Signal · October 2006 Featured Publication Protein phosphatase-1 (PP1), through interactions with substrate targeting subunits, plays critical roles in the regulation of numerous cellular processes. Herein, we describe a newly identified regulatory subunit (PITK; Phosphatase Interactor Targeting K ... Full text Link to item Cite

Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice.

Journal Article J Clin Invest · August 2006 The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structu ... Full text Link to item Cite

A role for PP1 in the Cdc2/Cyclin B-mediated positive feedback activation of Cdc25.

Journal Article Mol Biol Cell · April 2006 The Cdc25 phosphatase promotes entry into mitosis through the removal of inhibitory phosphorylations on the Cdc2 subunit of the Cdc2/CyclinB complex. During interphase, or after DNA damage, Cdc25 is suppressed by phosphorylation at Ser287 (Xenopus numberin ... Full text Link to item Cite

Delineating signal transduction pathways in smooth muscle through focused proteomics.

Journal Article Expert Rev Proteomics · February 2006 This review will outline examples of the authors' focused proteomics approaches to studying signal transduction pathways in smooth muscle. By focusing the use of traditional proteomics techniques with hypothesis-driven selection methods, this approach effi ... Full text Link to item Cite

The purinome, a complex mix of drug and toxicity targets.

Journal Article Curr Top Med Chem · 2006 Much attention has focused on the development of protein kinases as drug targets to treat a variety of human diseases including diabetes, cancer, hypertension and arthritis. To date, Gleevec is one example of a drug targeting protein that has successfully ... Full text Link to item Cite

Affinity Purification with natural immobilized ligands

Chapter · November 16, 2005 This chapter discusses affinity chromatography-based techniques to examine protein interaction between other proteins or small ligands. The first procedure involves the use of toxin microcystin LR (MC-LR) conjugated to a biotin or Sepharose matrix to bioch ... Full text Cite

ZIP kinase, a key regulator of myosin protein phosphatase 1.

Journal Article Cell Signal · November 2005 Two major physiological roles have been defined for zipper interacting protein kinase (ZIPK), regulation of apoptosis in non-muscle cells and regulation of Ca(2+) sensitization in smooth muscle. Although much attention has focused on the role of ZIPK in th ... Full text Link to item Cite

Mammalian septins regulate microtubule stability through interaction with the microtubule-binding protein MAP4.

Journal Article Mol Biol Cell · October 2005 Mammalian septins constitute a family of at least 12 GTP-binding proteins that can form hetero-oligomers and that are sometimes found in association with actin or microtubule filaments. However, their functions are not understood. Using RNA interference, w ... Full text Link to item Cite

Caspase-3 dependent cleavage and activation of skeletal muscle phosphorylase b kinase.

Journal Article Mol Cell Biochem · July 2005 Phosphorylase b kinase (PhK) is a key enzyme involved in the conversion of glycogen to glucose in skeletal muscle and ultimately an increase in intracellular ATP. Since apoptosis is an ATP-dependent event, we investigated the regulation of skeletal muscle ... Full text Link to item Cite

Regulation of zipper-interacting protein kinase activity in vitro and in vivo by multisite phosphorylation.

Journal Article J Biol Chem · March 11, 2005 Featured Publication Zipper-interacting protein kinase (ZIPK) is a widely expressed serine/threonine kinase implicated in cell death and smooth muscle contractility, but its mechanism of regulation is unknown. We have identified six phosphorylation sites in ZIPK that regulate ... Full text Link to item Cite

The proteome

Journal Article · December 20, 2004 Cite

Changes in magnetization transfer MRI correlate with spreading depression-induced astroglial reactivity and increased protein expression in mice.

Journal Article AJR Am J Roentgenol · December 2004 OBJECTIVE: Gliosis refers to a range of glial cell transformations that vary according to specific brain pathologic states. Disease, however, is not a prerequisite for gliosis because glial reactivity may also be seen in regions of increased physiologic ac ... Full text Link to item Cite

Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins.

Journal Article FEBS Lett · August 27, 2004 Cyclic nucleotides acting through their associated protein kinases, the cGMP- and cAMP-dependent protein kinases, can relax smooth muscles without a change in free intracellular calcium concentration ([Ca2+]i), a phenomenon referred to as Ca2+ desensitizat ... Full text Link to item Cite

Smooth muscle phosphatase is regulated in vivo by exclusion of phosphorylation of threonine 696 of MYPT1 by phosphorylation of Serine 695 in response to cyclic nucleotides.

Journal Article J Biol Chem · August 13, 2004 Featured Publication Regulation of smooth muscle myosin phosphatase (SMPP-1M) is thought to be a primary mechanism for explaining Ca(2+) sensitization/desensitization in smooth muscle. Ca(2+) sensitization induced by activation of G protein-coupled receptors acting through Rho ... Full text Link to item Cite

A feedback loop in the polo-like kinase activation pathway.

Journal Article J Biol Chem · July 30, 2004 The Xenopus polo-like kinase Plx1 plays important roles during entry into and exit from mitosis (M phase). Previous studies revealed that Plx1 is activated by phosphorylation on serine and threonine residues, and purification of an activating enzyme from m ... Full text Link to item Cite

C-terminal repeat domain kinase I phosphorylates Ser2 and Ser5 of RNA polymerase II C-terminal domain repeats.

Journal Article J Biol Chem · June 11, 2004 The C-terminal repeat domain (CTD) of the largest subunit of RNA polymerase II is composed of tandem heptad repeats with consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. In yeast, this heptad sequence is repeated about 26 times, and it becomes hyperp ... Full text Link to item Cite

Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines.

Journal Article Biochemistry · April 20, 2004 Featured Publication Quinone oxidoreductase 2 (QR2) purified from human red blood cells was recently shown to be a potential target of the quinoline antimalarial compounds [Graves et al., (2002) Mol. Pharmacol. 62, 1364]. QR2 catalyzes the two-electron reduction of menadione v ... Full text Link to item Cite

CRP: Cleavage of Radiolabeled Phosphoproteins.

Journal Article Nucleic Acids Res · July 1, 2003 The CRP (Cleavage of Radiolabeled Phosphoproteins) program guides the design and interpretation of experiments to identify protein phosphorylation sites by Edman sequencing of unseparated peptides. Traditionally, phosphorylation sites are determined by cle ... Full text Link to item Cite

Comparative analysis of the ATP-binding sites of Hsp90 by nucleotide affinity cleavage: a distinct nucleotide specificity of the C-terminal ATP-binding site.

Journal Article Eur J Biochem · June 2003 The 90-kDa heat shock protein (Hsp90) is a molecular chaperone that assists both in ATP-independent sequestration of damaged proteins, and in ATP-dependent folding of numerous targets, such as nuclear hormone receptors and protein kinases. Recent work from ... Full text Link to item Cite

SLLP1, a unique, intra-acrosomal, non-bacteriolytic, c lysozyme-like protein of human spermatozoa.

Journal Article Biol Reprod · May 2003 We report the presence of a unique, non-bacteriolytic, c (chicken or conventional type) lysozyme-like protein, SLLP1, in the acrosome of human sperm. C lysozymes are bacteriolytic and can also bind to N-acetylglucosamines linked by beta-1,4 glycosidic bond ... Full text Link to item Cite

Proteomic analysis of calcium/calmodulin-dependent protein kinase I and IV in vitro substrates reveals distinct catalytic preferences.

Journal Article J Biol Chem · March 21, 2003 The multifunctional calcium/calmodulin-dependent protein kinases I and IV (CaMKI and CaMKIV) are closely related by primary sequence and predicted to have similar substrate specificities based on peptide studies. We identified a fragment of p300-(1-117) th ... Full text Link to item Cite

A functional proteomics approach to signal transduction.

Journal Article Recent Prog Horm Res · 2003 The purpose of this review is to highlight how proteomics techniques can be used to answer specific questions related to signal transduction in a wide variety of systems. In our laboratory, we utilize proteomic technologies to elucidate signal transduction ... Full text Link to item Cite

Phosphoproteome analysis in yeast.

Journal Article Methods Enzymol · 2003 Full text Link to item Cite

Discovery of novel targets of quinoline drugs in the human purine binding proteome.

Journal Article Mol Pharmacol · December 2002 The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear. In this study, we used a functional proteomics approach that exploited the structural similarities be ... Full text Link to item Cite

Phosphorylation of the myosin phosphatase target subunit by integrin-linked kinase.

Journal Article Biochem J · August 15, 2002 A mechanism proposed for regulation of myosin phosphatase (MP) activity is phosphorylation of the myosin phosphatase target subunit (MYPT1). Integrin-linked kinase (ILK) is associated with the contractile machinery and can phosphorylate myosin at the myosi ... Full text Link to item Cite

Smooth muscle myosin phosphatase-associated kinase induces Ca2+ sensitization via myosin phosphatase inhibition.

Journal Article J Biol Chem · June 28, 2002 Featured Publication Smooth muscle calcium sensitization reflects an inhibition of myosin light chain phosphatase (SMPP-1m) activity; however, the underlying mechanisms are not well understood. SMPP-1m activity can be modulated through phosphorylation of the myosin targeting s ... Full text Link to item Cite

A strategy for the rapid identification of phosphorylation sites in the phosphoproteome.

Journal Article Mol Cell Proteomics · April 2002 Edman phosphate ((32)P) release sequencing provides a high sensitivity means of identifying phosphorylation sites in proteins that complements mass spectrometry techniques. We have developed a bioinformatic assessment tool, the cleavage of radiolabeled pro ... Full text Link to item Cite

Molecular biologist's guide to proteomics.

Journal Article Microbiol Mol Biol Rev · March 2002 Featured Publication The emergence of proteomics, the large-scale analysis of proteins, has been inspired by the realization that the final product of a gene is inherently more complex and closer to function than the gene itself. Shortfalls in the ability of bioinformatics to ... Full text Link to item Cite

Caspase-dependent cleavage of carbamoyl phosphate synthetase II during apoptosis.

Journal Article Mol Pharmacol · March 2002 Carbamoyl phosphate synthetase II (CPSII) is part of carbamoyl phosphate synthetase/aspartate transcarbamoylase/dihydroorotase (CAD), a multienzymatic protein required for the de novo synthesis of pyrimidine nucleotides and cell growth. Herein, we identify ... Full text Link to item Cite

Getting more from less: algorithms for rapid protein identification with multiple short peptide sequences.

Journal Article Mol Cell Proteomics · February 2002 We describe two novel sequence similarity search algorithms, FASTS and FASTF, that use multiple short peptide sequences to identify homologous sequences in protein or DNA databases. FASTS searches with peptide sequences of unknown order, as obtained by mas ... Full text Link to item Cite

Borg proteins control septin organization and are negatively regulated by Cdc42.

Journal Article Nat Cell Biol · October 2001 The Cdc42 GTPase binds to numerous effector proteins that control cell polarity, cytoskeletal remodelling and vesicle transport. In many cases the signalling pathways downstream of these effectors are not known. Here we show that the Cdc42 effectors Borg1 ... Full text Link to item Cite

Site-specific phosphorylation and point mutations of telokin modulate its Ca2+-desensitizing effect in smooth muscle.

Journal Article J Biol Chem · July 6, 2001 Forskolin and 8-bromoguanosine 3'-5'-cyclic monophosphate (8-Br-cGMP) induce phosphorylation of Ser-13 of telokin and relaxation of smooth muscle at constant calcium. Comparison with the effect of wild type with aspartate (D; to mimic phosphorylation) and ... Full text Link to item Cite

A role for the Ppz Ser/Thr protein phosphatases in the regulation of translation elongation factor 1Balpha.

Journal Article J Biol Chem · May 4, 2001 In vivo 32P-labeled yeast proteins from wild type and ppz1 ppz2 phosphatase mutants were resolved by bidimensional electrophoresis. A prominent phosphoprotein, which in ppz mutants showed a marked shift to acidic regions, was identified by mixed peptide se ... Full text Link to item Cite

Dual Ser and Thr phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by MYPT-associated kinase.

Journal Article FEBS Lett · March 30, 2001 Phosphorylation of CPI-17 and PHI-1 by the MYPT1-associated kinase (M110 kinase) was investigated. M110 kinase is a recently identified serine/threonine kinase with a catalytic domain that is homologous to that of ZIP kinase (ZIPK. GST-rN-ZIPK, a constitut ... Full text Link to item Cite

Identification of the endogenous smooth muscle myosin phosphatase-associated kinase.

Journal Article Proc Natl Acad Sci U S A · February 27, 2001 Ca(2+) sensitization of smooth muscle contraction involves inhibition of myosin light chain phosphatase (SMPP-1M) and enhanced myosin light chain phosphorylation. Inhibition of SMPP-1M is modulated through phosphorylation of the myosin targeting subunit (M ... Full text Link to item Cite

Phosphorylation of telokin by cyclic nucleotide kinases and the identification of in vivo phosphorylation sites in smooth muscle.

Journal Article FEBS Lett · August 18, 2000 The Ca(2+)-independent acceleration of dephosphorylation of the regulatory light chain of smooth muscle myosin and relaxation of smooth muscle by telokin are enhanced by cyclic nucleotide-activated protein kinase(s) [Wu et al. (1998) J. Biol. Chem. 273, 11 ... Full text Link to item Cite

Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression.

Journal Article Mol Cell Biol · May 2000 Control of the translational repressor, PHAS-I, was investigated by expressing proteins with Ser/Thr --> Ala mutations in the five (S/T)P phosphorylation sites. Results of experiments with HEK293 cells reveal at least three levels of control. At one extrem ... Full text Link to item Cite

Regulatory interactions between the Reg1-Glc7 protein phosphatase and the Snf1 protein kinase.

Journal Article Mol Cell Biol · February 2000 Protein phosphatase 1, comprising the regulatory subunit Reg1 and the catalytic subunit Glc7, has a role in glucose repression in Saccharomyces cerevisiae. Previous studies showed that Reg1 regulates the Snf1 protein kinase in response to glucose. Here, we ... Full text Link to item Cite

Neurofilament-L is a protein phosphatase-1-binding protein associated with neuronal plasma membrane and post-synaptic density.

Journal Article J Biol Chem · January 28, 2000 Far Westerns with digoxigenin-conjugated protein phosphatase-1 (PP1) catalytic subunit identified PP1-binding proteins in extracts from bovine, rat, and human brain. A major 70-kDa PP1-binding protein was purified from bovine brain cortex plasma membranes, ... Full text Link to item Cite

Reg1p targets protein phosphatase 1 to dephosphorylate hexokinase II in Saccharomyces cerevisiae: characterizing the effects of a phosphatase subunit on the yeast proteome.

Journal Article EMBO J · August 2, 1999 Protein phosphatase 1 (Glc7p) and its binding protein Reg1p are essential for the regulation of glucose repression pathways in Saccharomyces cerevisiae. In order to identify physiological substrates for the Glc7p-Reg1p complex, we examined the effects of d ... Full text Link to item Cite

Phosphorylation of the rRNA transcription factor upstream binding factor promotes its association with TATA binding protein.

Journal Article Proc Natl Acad Sci U S A · December 8, 1998 rRNA synthesis by RNA polymerase I requires both the promoter selectivity factor 1, which is composed of TATA binding protein (TBP) and three TBP-associated factors, and the activator upstream binding factor (UBF). Whereas there is strong evidence implicat ... Full text Link to item Cite

Rapid identification of protein phosphatase 1-binding proteins by mixed peptide sequencing and data base searching. Characterization of a novel holoenzymic form of protein phosphatase 1.

Journal Article J Biol Chem · September 18, 1998 Microcystin-affinity chromatography was used to purify 15 protein phosphatase 1 (PP1)-binding proteins from the myofibrillar fraction of rabbit skeletal muscle. To reduce the time and amount of material required to identify these proteins, proteome analysi ... Full text Link to item Cite

Phosphorylation of the translational regulator, PHAS-I, by protein kinase CK2.

Journal Article FEBS Lett · September 11, 1998 The primary site in PHAS-I for phosphorylation by protein kinase CK2 in vitro was identified as Ser111. A relatively small amount of phosphorylation of Ser99 was also detected, and mutating Ser99 to Ala in PHAS-I slightly decreased phosphorylation by CK2 i ... Full text Link to item Cite

Acceleration of myosin light chain dephosphorylation and relaxation of smooth muscle by telokin. Synergism with cyclic nucleotide-activated kinase.

Journal Article J Biol Chem · May 1, 1998 Incorporation of 32P into telokin, a smooth muscle-specific, 17-18-kDa, acidic (pI 4.2-4.4) protein, was increased by forskolin (20 microM) in intact rabbit ileum smooth muscle (ileum) and by 8-bromo-cyclic GMP (100 microM) in alpha-toxin-permeabilized ile ... Full text Link to item Cite

Okadaic acid in New Zealand sponges: Detection by cytotoxicity, protein phosphatase inhibition and immunoassay techniques

Journal Article Natural Product Letters · January 1, 1998 Using a combination of P388 cytotoxicity testing, protein phosphatase enzyme inhibition assays and an ELISA immunoassay, okadaic acid, the causative agent of diarrhetic shellfish poisoning (DSP), has been found in Raspalia agminata, and detected in two oth ... Full text Cite

The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus.

Journal Article J Biol Chem · December 19, 1997 The eukaryotic initiation factor 4E (eIF4E)-binding protein, PHAS-I, was phosphorylated rapidly and stoichiometrically when incubated with [gamma-32P]ATP and the mammalian target of rapamycin (mTOR) that had been immunoprecipitated with an antibody, mTAb1, ... Full text Link to item Cite

Activation of MAPK by MEK is enhanced by a thioltransferase

Journal Article FASEB Journal · December 1, 1997 Recently we purified to homogeneity a MEK enhancing factor (MEF) that stimulates the rate of MAPK phosphorylation by MEK. In the presence of MKF, molar equivalents of MEK to MAPK were sufficient for MAPK phosphorylation to stoichiometric levels. MEE was id ... Cite

The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation.

Journal Article J Biol Chem · September 19, 1997 Many functions of the chaperone, heat shock protein 90 (hsp90), are inhibited by the drug geldanamycin that specifically binds hsp90. We have studied an amino-terminal domain of hsp90 whose crystal structure has recently been solved and determined to conta ... Full text Link to item Cite

Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes.

Journal Article J Biol Chem · April 11, 1997 Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase in vitro decreased PHAS-I binding to eukaryotic initiation factor (eIF)-4E. The decrease in binding lagged behind the phosphorylation of PHAS-I in Ser64, the preferred site of MAP kinase. ... Full text Link to item Cite

Endothelial cell-conditioned medium downregulates smooth muscle contractile protein expression.

Journal Article Am J Physiol · February 1997 Smooth muscle cells (SMC) within atherosclerotic lesions proliferate and exhibit phenotypic modulation, but the contribution of vascular endothelium to this process is poorly understood. Our aim was to examine the effects of endothelial cell-conditioned me ... Full text Link to item Cite

Telokin relaxes smooth muscle and is phosphorylated, in situ

Journal Article BIOPHYSICAL JOURNAL · February 1, 1997 Link to item Cite

PHAS proteins as mediators of the actions of insulin, growth factors and cAMP on protein synthesis and cell proliferation.

Journal Article Adv Enzyme Regul · 1997 PHAS-I and PHAS-II are members of a newly discovered family of proteins that regulate translation initiation. PHAS-I is expressed in a wide variety of cell types, but it is highest in adipocytes, where protein synthesis is markedly increased by insulin. PH ... Full text Link to item Cite

Effects of insulin and diabetes on the association of eukaryotic initiation factor 4e and the translational regulator, phas-i, in rat skeletal muscle

Journal Article FASEB Journal · December 1, 1996 Our previous studies have shown that protein synthesis is inhibited in rat skeletal muscle during diabetes and that the inhibition is rapidly reversed by insulin treatment of diabetic rats. In the present study, we have investigated the roles of the cap-bi ... Cite

Protein phosphatase 2a is involved in regulation of the secondary sustained phase of map kinase activity in response to vascular smooth muscle hypertrophic and mitogenic stimuli

Journal Article FASEB Journal · December 1, 1996 Angiotensin II (A-II) and cc-thrombin are growth factors that have been previously shown in this laboratory to induce hypertrophy and mitogenesis of cultured vascular smooth muscle cells (VSMC), respectively. The intracellular signaling pathways through wh ... Cite

Identification of protein phosphatase-1-binding proteins by microcystin-biotin affinity chromatography.

Journal Article J Biol Chem · November 8, 1996 Biotinylated microcystin was used to affinity purify over avidin-Sepharose the entire cellular content of active forms of protein phosphatase (PP) 1 and 2A holoenzymes present in three subcellular fractions of skeletal muscle. Biotinylated microcystin disp ... Full text Link to item Cite

Regions of the 110-kDa regulatory subunit M110 required for regulation of myosin-light-chain-phosphatase activity in smooth muscle.

Journal Article Eur J Biochem · July 15, 1996 To characterize the in situ interactions between the subunits (regulatory 110 kDa, M110; 21-kDa, M21 and catalytic, 37-kDa, PP1c) of smooth muscle myosin phosphatase (SMPP-1M), we determined, in Triton-X-100-permeabilized rabbit portal vein contracted with ... Full text Link to item Cite

Insulin and diabetes cause reciprocal changes in the association of eIF-4E and PHAS-I in rat skeletal muscle.

Journal Article Am J Physiol · February 1996 We have investigated the roles of eukaryotic initiation factor 4E (eIF-4E), the cap-binding protein, and the translational regulator, PHAS-I, in the effects of insulin and alloxan-induced diabetes on protein synthesis in rat skeletal muscle. Diabetes incre ... Full text Link to item Cite

Insulin and diabetes cause reciprocal changes in the association of eIF-4E and PHAS-I in rat skeletal muscle

Journal Article AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY · February 1, 1996 Link to item Cite

Molecular cloning and functional expression of a recombinant 72.5 kDa fragment of the 110 kDa regulatory subunit of smooth muscle protein phosphatase 1M.

Journal Article FEBS Lett · December 18, 1995 We have cloned a partial rat kidney cDNA that encodes a 72.5 kDa N terminal fragment of a third isoform of the M110 subunit of phosphatase 1. This new isoform contains an insert in the 542-597 position not present in the M110 previously cloned (Chen et al. ... Full text Link to item Cite

Angiotensin II-induced hypertrophy of rat vascular smooth muscle is associated with increased 18 S rRNA synthesis and phosphorylation of the rRNA transcription factor, upstream binding factor.

Journal Article J Biol Chem · October 20, 1995 Hypertrophy of vascular smooth muscle cells (VSMC) is an important adaptive response of hypertension. Drug intervention studies have implicated a role for angiotensin II (A-II) in the mediation of VSMC hypertrophy in vivo, and A-II is a potent hypertrophic ... Full text Link to item Cite

Purification of a 12,020-dalton protein that enhances the activation of mitogen-activated protein (MAP) kinase by MAP kinase kinase.

Journal Article J Biol Chem · October 13, 1995 We have purified 3500-fold from rabbit skeletal muscle a 12,020-Da mitogen-activated protein kinase kinase (MEK)-enhancing factor (MEF) that stimulates both mitogen-activated protein kinase (MAPK) autophosphorylation and the rate (24-fold) at which the enz ... Full text Link to item Cite

Phosphorylation of caldesmon by mitogen-activated protein kinase with no effect on Ca2+ sensitivity in rabbit smooth muscle.

Journal Article J Physiol · September 1, 1995 1. Recombinant, activated mitogen-activated protein kinase (3.3 microM; p42mapk) phosphorylated caldesmon in phasic (rabbit portal vein) and tonic (rabbit femoral artery) smooth muscle strips permeabilized with Triton X-100. 2. Phosphorylation of caldesmon ... Full text Link to item Cite

Quantitative and selective fluorophore labeling of phosphoserine on peptides and proteins: characterization at the attomole level by capillary electrophoresis and laser-induced fluorescence.

Journal Article Anal Biochem · February 10, 1995 Reaction conditions were defined for the selective quantitative derivatization and fluorophore labeling of phosphoserine residues on peptides and proteins. Phosphoserine was derivatized with 1,2-ethanedithiol using a modification of the reaction conditions ... Full text Link to item Cite

Purification and characterization of the mammalian myosin light chain phosphatase holoenzyme. The differential effects of the holoenzyme and its subunits on smooth muscle.

Journal Article J Biol Chem · December 16, 1994 We have purified to homogeneity from the myofibrillar fraction of pig bladder a mammalian heterotrimeric form of PP-1, SMPP-1M. Purified pig bladder SMPP-1M is similar in composition and substrate specificity to avian gizzard PP-1M reported by Alessi et al ... Link to item Cite

PHAS-I as a link between mitogen-activated protein kinase and translation initiation.

Journal Article Science · October 28, 1994 PHAS-I is a heat-stable protein (relative molecular mass approximately 12,400) found in many tissues. It is rapidly phosphorylated in rat adipocytes incubated with insulin or growth factors. Nonphosphorylated PHAS-I bound to initiation factor 4E (eIF-4E) a ... Full text Link to item Cite

Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes.

Journal Article J Biol Chem · September 16, 1994 PHAS-I is a heat- and acid-stable protein that is phosphorylated on Ser/Thr residues in response to insulin and growth factors. To investigate the phosphorylation of PHAS-I, the protein was expressed in bacteria and purified for use as substrate in protein ... Link to item Cite

Purification of the AMP-activated protein kinase on ATP-gamma-sepharose and analysis of its subunit structure.

Journal Article Eur J Biochem · July 15, 1994 The AMP-activated protein kinase has been purified by affinity chromatography on ATP-gamma-Sepharose. A proportion of the activity can be eluted using AMP, while the remainder is eluted using ATP. The AMP eluate contains three polypeptides of 63, 38 and 35 ... Full text Link to item Cite

Insulin activates a novel adipocyte mitogen-activated protein kinase kinase kinase that shows rapid phasic kinetics and is distinct from c-Raf.

Journal Article J Biol Chem · April 29, 1994 Treatment of adipocytes with insulin or phorbol 12-myristate 13-acetate (PMA) results in transient activation of mitogen-activated protein kinase kinase (MEK) (Tmax = 90 s) and mitogen-activated protein kinase (MAPK) (Tmax = 300 s). We have identified a no ... Link to item Cite

Gamma-phosphate-linked ATP-sepharose for the affinity purification of protein kinases. Rapid purification to homogeneity of skeletal muscle mitogen-activated protein kinase kinase.

Journal Article Eur J Biochem · June 1, 1993 Recently, Sowadski and colleagues [Knighton, D.R., Zheng, J., Eyck, L.F.T., Ashford, V.A., Xuong, N., Taylor, S.S. & Sowadski, J.M. (1991) Science 407, 407-420] reported the structure of a ternary complex of the catalytic subunit of cAMP-dependent protein ... Full text Link to item Cite

Functional expression of a MAP kinase kinase in COS cells and recognition by an anti-STE7/byr1 antibody.

Journal Article FEBS Lett · February 8, 1993 Mitogen-activated protein (MAP) kinases p42mapk and p44mapk are activated by dual tyrosine and threonine phosphorylation in vivo. Both MAPKs are phosphorylated and activated in vitro by an activator recently identified as a protein-tyrosine/threonine kinas ... Full text Link to item Cite

Molecular structure of a protein-tyrosine/threonine kinase activating p42 mitogen-activated protein (MAP) kinase: MAP kinase kinase.

Journal Article Proc Natl Acad Sci U S A · January 1, 1993 MAP kinases p42mapk and p44mapk participate in a protein kinase cascade(s) important for signaling in many cell types and contexts. Both MAP kinases are activated in vitro by MAP kinase kinase, a protein-tyrosine and threonine kinase. A MAP kinase kinase c ... Full text Link to item Cite

Activation of MAP kinase by a dual specificity Tyr/Thr kinase.

Journal Article Adv Second Messenger Phosphoprotein Res · 1993 Link to item Cite

Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro.

Journal Article Science · September 4, 1992 Mitogen-activated protein (MAP) kinases are 42- and 44-kD serine-threonine protein kinases that are activated by tyrosine and threonine phosphorylation in cells stimulated with mitogens and growth factors. MAP kinase and the protein kinase that activates i ... Full text Link to item Cite

Renaturation and partial peptide sequencing of mitogen-activated protein kinase (MAP kinase) activator from rabbit skeletal muscle.

Journal Article Biochem J · August 1, 1992 Mitogen-activated protein kinase (MAP kinase) activator was purified 2000-fold from skeletal muscle, and proteins which co-purified with the activator were analysed after SDS/PAGE by renaturation and partial sequencing. Activity for tyrosine and threonine ... Full text Link to item Cite

Ordered phosphorylation of p42mapk by MAP kinase kinase.

Journal Article FEBS Lett · July 13, 1992 Preparation of milligram amounts of [32P]p42mapk, phosphorylated at Tyr185 or diphosphorylated at Tyr185/Thr183, for use as specific protein phosphatase substrates is described. Tyr- but not Thr-phosphorylated p42mapk, accumulates when ATP is limiting. Fur ... Full text Link to item Cite

Activation of messenger-independent protein kinases in wild-type and phorbol ester-resistant EL4 thymoma cells.

Journal Article J Biol Chem · January 25, 1991 Phorbol esters, acting via activation of the protein kinase C family of protein serine/threonine kinases, are able to exert profound effects on various cellular functions. In this study, we used the EL4 thymoma cell line to study the potential role of "dow ... Link to item Cite

Okadaic acid mimics the action of insulin in stimulating protein kinase activity in isolated adipocytes. The role of protein phosphatase 2a in attenuation of the signal.

Journal Article J Biol Chem · September 25, 1990 Treatment of adipocytes with okadaic acid (a specific inhibitor of type 1 and 2a protein phosphatases) resulted in a rapid 8-10-fold stimulation of cell extract myelin basic protein (MBP) kinase activity (t1/2 = 10 min) and kinase activity toward a synthet ... Link to item Cite

Roles of the AMP-activated and cyclic-AMP-dependent protein kinases in the adrenaline-induced inactivation of acetyl-CoA carboxylase in rat adipocytes.

Journal Article Eur J Biochem · January 12, 1990 1. In isolated rat adipocytes, acetyl-CoA carboxylase is inactivated by treatment of the cells with adrenaline or the beta-agonist isoproterenol, but not by the alpha-agonist phenylephrine. The inactivation is stable during purification in the presence of ... Full text Link to item Cite

Effects of the tumour promoter okadaic acid on intracellular protein phosphorylation and metabolism.

Journal Article Nature · January 5, 1989 Okadaic acid is a polyether derivative of 38-carbon fatty acid, and is implicated as the causative agent of diarrhetic shellfish poisoning. It is a potent tumour promoter that is not an activator of protein kinase C, but is a powerful inhibitor of protein ... Full text Link to item Cite

Epidermal growth factor alters metabolism of inositol lipids and activity of protein kinase C in mouse embryo palate mesenchyme cells.

Journal Article J Craniofac Genet Dev Biol · 1989 Epidermal growth factor (EGF) stimulated mouse embryo palate mesenchyme (MEPM) cells (1) to incorporate [32P]O4(3-) into phosphatidylinositol (PI), phosphatidylcholine, and phosphatidic acid over a period of 60 min; 2) to incorporate [32P]O4(3-) into polyp ... Link to item Cite

Analysis of sites phosphorylated on acetyl-CoA carboxylase in response to insulin in isolated adipocytes. Comparison with sites phosphorylated by casein kinase-2 and the calmodulin-dependent multiprotein kinase.

Journal Article Eur J Biochem · August 1, 1988 We have examined the sites phosphorylated on acetyl-CoA carboxylase in response to insulin in isolated adipocytes. Two tryptic peptides derived from the enzyme become more radioactive after treatment of 32P-labelled cells with insulin. One of these (T4a) a ... Full text Link to item Cite

Insulin and phorbol ester stimulate phosphorylation of acetyl-CoA carboxylase at similar sites in isolated adipocytes. Lack of correspondence with sites phosphorylated on the purified enzyme by protein kinase C.

Journal Article Eur J Biochem · August 1, 1988 1. The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) stimulates fatty acid synthesis from glucose in isolated adipocytes with a half-maximal effect at 0.72 microM. In seven batches of cells, the maximal effects of TPA and insulin were 8.5 +/- 1 ... Full text Link to item Cite

ACTIVATION OF ACETYL-COA CARBOXYLASE BY INSULIN-ALLOSTERIC EFFECT OR PROTEIN-PHOSPHORYLATION

Journal Article ARCHIVES INTERNATIONALES DE PHYSIOLOGIE DE BIOCHIMIE ET DE BIOPHYSIQUE · December 1, 1987 Link to item Cite

Evidence that activation of acetyl-CoA carboxylase by insulin in adipocytes is mediated by a low-Mr effector and not by increased phosphorylation.

Journal Article Biochem J · November 15, 1986 The activation of acetyl-CoA carboxylase (measured in a crude supernatant fraction) caused by insulin treatment of adipocytes was completely unaffected by the addition of a large amount of highly purified protein phosphatase to the supernatant fraction. Un ... Full text Link to item Cite

Both insulin and epidermal growth factor stimulate lipogenesis and acetyl-CoA carboxylase activity in isolated adipocytes. Importance of homogenization procedure in avoiding artefacts in acetyl-CoA carboxylase assay.

Journal Article Biochem J · March 1, 1986 Epidermal growth factor (EGF) stimulates lipogenesis by 3-4-fold in isolated adipocytes, with a half-maximal effect at 10 nM-EGF. In the same batches of cells insulin stimulated lipogenesis by 15-fold. Freezing and prolonged homogenization of adipocytes re ... Full text Link to item Cite

Further consideration of the learning impairment after aceperone in the marmoset: effects of the drug on shape and colour discrimination and on an alternation task.

Journal Article Pharmacol Biochem Behav · May 1983 Ten marmosets (Callithrix jacchus) learned to discriminate between pairs of small grey objects differing only in shape or small plain plaques differing only in colour, in a Wisconsin General Test Apparatus. Each day, each animal was presented with three co ... Full text Link to item Cite

A new approach to the role of noradrenaline in learning: problem-solving in the marmoset after alpha-noradrenergic receptor blockade.

Journal Article Pharmacol Biochem Behav · June 1981 Nine marmosets (Callithrix jacchus) were tested on a variety of visual discrimination learning tasks in a Wisconsin General Test Apparatus with or without alpha-noradrenergic receptor blockade achieved by the administration of aceperone. After aceperone, a ... Full text Link to item Cite

An analysis of visual object reversal learning in the marmoset after amphetamine and haloperidol.

Journal Article Pharmacol Biochem Behav · March 1981 The effect of amphetamine and haloperidol pretreatment on visual object reversal learning was assessed in the marmoset. Amphetamine induced perseverative responding demonstrated by high reversal learning scores and worse than chance performance in the earl ... Full text Link to item Cite

An involvement of dopamine in higher order choice mechanisms in the monkey.

Journal Article Psychopharmacology (Berl) · 1981 Low doses of amphetamine induce choice perseveration in an object discrimination task under conditions where such perseveration either increases or decreases the number of rewards obtained as compared to chance performance. Neither stereotyped motor action ... Full text Link to item Cite

Perseverative behaviour after amphetamine; dissociation of response tendency from reward association.

Journal Article Psychopharmacology (Berl) · 1981 Low doses of amphetamine were found to alter the ability of marmosets to take account of changes in reward values of object stimuli in a visual discrimination task. Under amphetamine, animals changed their motor responses and stimulus choice in order to pr ... Full text Link to item Cite

"Go here-to there" performance after amphetamine: the importance of the response requirement in successive discrimination.

Journal Article Psychopharmacology (Berl) · 1980 Marmosets were trained on a task involving simultaneous and successive visual discrimination performance where responses were required on all trials. Performance of this task was not affected by low doses of amphetamine. From this it is concluded that amph ... Full text Link to item Cite