Scholars@Duke
David Marc Virshup

David Marc Virshup

Professor of Pediatrics
Pediatrics
david.virshup@duke.edu
Box 2927 Med Ctr, Durham, NC 27710
128 Davison Bldg, Durham, NC 27710
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Selected Publications

Ultra-large scale virtual screening identifies a small molecule inhibitor of the Wnt transporter Wntless.

Journal Article iScience · August 16, 2024 Wnts are lipid-modified glycoproteins that play key roles in both embryonic development and adult homeostasis. Wnt signaling is dysregulated in many cancers and preclinical data shows that targeting Wnt biosynthesis and secretion can be effective in Wnt-ad ... Full text Link to item Cite

Hierarchical and scaffolded phosphorylation of two degrons controls PER2 stability.

Journal Article J Biol Chem · June 2024 The duration of the transcription-repression cycles that give rise to mammalian circadian rhythms is largely determined by the stability of the PERIOD (PER) protein, the rate-limiting components of the molecular clock. The degradation of PERs is tightly re ... Full text Link to item Cite

Pushing the Frontiers of Cancer Research: Highlights from the Frontiers in Cancer Science Conference 2023.

Journal Article Cancer Res · April 15, 2024 The 15th annual Frontiers in Cancer Science (FCS) conference gathered scientific experts who shared the latest research converging upon several themes of cancer biology. These themes included the dysregulation of metabolism, cell death, and other signaling ... Full text Link to item Cite

Recurrent mutations in tumor suppressor FBXW7 bypass Wnt/β-catenin addiction in cancer.

Journal Article Sci Adv · April 5, 2024 Pathologic Wnt/β-catenin signaling drives various cancers, leading to multiple approaches to drug this pathway. Appropriate patient selection can maximize success of these interventions. Wnt ligand addiction is a druggable vulnerability in RNF43-mutant/RSP ... Full text Link to item Cite

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling.

Journal Article J Clin Invest · January 23, 2024 Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 dem ... Full text Link to item Cite

Abstract P183: Porcupine Protects The Kidney By Suppressing Tubular Inflammation And Preserving Mitochondrial Integrity

Conference Hypertension · September 2023 Chronic Kidney Disease (CKD) progression may be slowed or stopped with early diagnosis and intervention, so developing novel therapies is paramount. The Wnt acyl transferase porcupine (PORCN) regulates the secretion of all 19 Wnt ligan ... Full text Cite

PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.

Journal Article Mol Cell · May 18, 2023 PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the familial advanced sleep phase (FASP) serine cluster embedded within ... Full text Link to item Cite

ETC-159, an Upstream Wnt inhibitor, Induces Tumour Necrosis via Modulation of Angiogenesis in Osteosarcoma.

Journal Article Int J Mol Sci · March 1, 2023 There is an increasing urgency in the search for new drugs to target high-grade cancers such as osteosarcomas (OS), as these have limited therapeutic options and poor prognostic outlook. Even though key molecular events leading to tumorigenesis are not wel ... Full text Link to item Cite

Functional regulation of Wnt protein through post-translational modifications.

Journal Article Biochem Soc Trans · December 16, 2022 Wnts are lipid-modified signaling glycoproteins present in all metazoans that play key roles in development and homeostasis. Post-translational modifications of Wnts regulate their function. Wnts have a unique post-translational modification, O-linked palm ... Full text Link to item Cite

A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models.

Journal Article J Clin Invest · June 15, 2022 Wnt signaling regulates the balance between stemness and differentiation in multiple tissues and in cancer. RNF43-mutant pancreatic cancers are dependent on Wnt production, and pharmacologic blockade of the pathway, e.g., by PORCN inhibitors, leads to tumo ... Full text Link to item Cite

Unearthing the Janus-face cholesterogenesis pathways in cancer.

Journal Article Biochemical pharmacology · February 2022 Cholesterol biosynthesis, primarily associated with eukaryotes, occurs as an essential component of human metabolism with biosynthetic deregulation a factor in cancer viability. The segment that partitions between squalene and the C27-end choles ... Full text Cite

An itch for things remote: The journey of Wnts.

Chapter · 2022 Wnts are a family of secreted, lipid-modified signaling glycoproteins that regulate a multiplicity of fundamental biological processes. Wnt signaling is essential for embryonic development, controlling body axis patterning, cell proliferation, cell migrati ... Full text Link to item Cite

Casein Kinase 1 and Human Disease: Insights From the Circadian Phosphoswitch.

Journal Article Front Mol Biosci · 2022 Biological systems operate in constant communication through shared components and feedback from changes in the environment. Casein kinase 1 (CK1) is a family of protein kinases that functions in diverse biological pathways and its regulation is beginning ... Full text Link to item Cite

Structural model of human PORCN illuminates disease-associated variants and drug-binding sites.

Journal Article J Cell Sci · December 15, 2021 Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential ... Full text Link to item Cite

A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion.

Journal Article N Engl J Med · September 30, 2021 BACKGROUND: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS: We queri ... Full text Link to item Cite

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

Journal Article Life Sci Alliance · May 2021 The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional targe ... Full text Link to item Cite

Ultra-large scale virtual screening identifies a small molecule inhibitor of the Wnt transporter Wntless.

Journal Article iScience · August 16, 2024 Wnts are lipid-modified glycoproteins that play key roles in both embryonic development and adult homeostasis. Wnt signaling is dysregulated in many cancers and preclinical data shows that targeting Wnt biosynthesis and secretion can be effective in Wnt-ad ... Full text Link to item Cite

Hierarchical and scaffolded phosphorylation of two degrons controls PER2 stability.

Journal Article J Biol Chem · June 2024 The duration of the transcription-repression cycles that give rise to mammalian circadian rhythms is largely determined by the stability of the PERIOD (PER) protein, the rate-limiting components of the molecular clock. The degradation of PERs is tightly re ... Full text Link to item Cite

Pushing the Frontiers of Cancer Research: Highlights from the Frontiers in Cancer Science Conference 2023.

Journal Article Cancer Res · April 15, 2024 The 15th annual Frontiers in Cancer Science (FCS) conference gathered scientific experts who shared the latest research converging upon several themes of cancer biology. These themes included the dysregulation of metabolism, cell death, and other signaling ... Full text Link to item Cite

Recurrent mutations in tumor suppressor FBXW7 bypass Wnt/β-catenin addiction in cancer.

Journal Article Sci Adv · April 5, 2024 Pathologic Wnt/β-catenin signaling drives various cancers, leading to multiple approaches to drug this pathway. Appropriate patient selection can maximize success of these interventions. Wnt ligand addiction is a druggable vulnerability in RNF43-mutant/RSP ... Full text Link to item Cite

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling.

Journal Article J Clin Invest · January 23, 2024 Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 dem ... Full text Link to item Cite

Abstract P183: Porcupine Protects The Kidney By Suppressing Tubular Inflammation And Preserving Mitochondrial Integrity

Conference Hypertension · September 2023 Chronic Kidney Disease (CKD) progression may be slowed or stopped with early diagnosis and intervention, so developing novel therapies is paramount. The Wnt acyl transferase porcupine (PORCN) regulates the secretion of all 19 Wnt ligan ... Full text Cite

PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.

Journal Article Mol Cell · May 18, 2023 PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the familial advanced sleep phase (FASP) serine cluster embedded within ... Full text Link to item Cite

ETC-159, an Upstream Wnt inhibitor, Induces Tumour Necrosis via Modulation of Angiogenesis in Osteosarcoma.

Journal Article Int J Mol Sci · March 1, 2023 There is an increasing urgency in the search for new drugs to target high-grade cancers such as osteosarcomas (OS), as these have limited therapeutic options and poor prognostic outlook. Even though key molecular events leading to tumorigenesis are not wel ... Full text Link to item Cite

Functional regulation of Wnt protein through post-translational modifications.

Journal Article Biochem Soc Trans · December 16, 2022 Wnts are lipid-modified signaling glycoproteins present in all metazoans that play key roles in development and homeostasis. Post-translational modifications of Wnts regulate their function. Wnts have a unique post-translational modification, O-linked palm ... Full text Link to item Cite

A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models.

Journal Article J Clin Invest · June 15, 2022 Wnt signaling regulates the balance between stemness and differentiation in multiple tissues and in cancer. RNF43-mutant pancreatic cancers are dependent on Wnt production, and pharmacologic blockade of the pathway, e.g., by PORCN inhibitors, leads to tumo ... Full text Link to item Cite

Unearthing the Janus-face cholesterogenesis pathways in cancer.

Journal Article Biochemical pharmacology · February 2022 Cholesterol biosynthesis, primarily associated with eukaryotes, occurs as an essential component of human metabolism with biosynthetic deregulation a factor in cancer viability. The segment that partitions between squalene and the C27-end choles ... Full text Cite

An itch for things remote: The journey of Wnts.

Chapter · 2022 Wnts are a family of secreted, lipid-modified signaling glycoproteins that regulate a multiplicity of fundamental biological processes. Wnt signaling is essential for embryonic development, controlling body axis patterning, cell proliferation, cell migrati ... Full text Link to item Cite

Casein Kinase 1 and Human Disease: Insights From the Circadian Phosphoswitch.

Journal Article Front Mol Biosci · 2022 Biological systems operate in constant communication through shared components and feedback from changes in the environment. Casein kinase 1 (CK1) is a family of protein kinases that functions in diverse biological pathways and its regulation is beginning ... Full text Link to item Cite

Structural model of human PORCN illuminates disease-associated variants and drug-binding sites.

Journal Article J Cell Sci · December 15, 2021 Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential ... Full text Link to item Cite

A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion.

Journal Article N Engl J Med · September 30, 2021 BACKGROUND: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS: We queri ... Full text Link to item Cite

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

Journal Article Life Sci Alliance · May 2021 The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional targe ... Full text Link to item Cite

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer.

Journal Article EMBO Mol Med · April 9, 2021 Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a ... Full text Link to item Cite

Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling.

Journal Article Nat Commun · April 6, 2021 Wnt signaling regulates cell proliferation and cell differentiation as well as migration and polarity during development. However, it is still unclear how the Wnt ligand distribution is precisely controlled to fulfil these functions. Here, we show that the ... Full text Link to item Cite

Cancer clocks in tumourigenesis: the p53 pathway and beyond.

Journal Article Endocr Relat Cancer · April 2021 Circadian rhythms regulate a vast array of physiological and cellular processes, as well as the hormonal milieu, to keep our cells synchronised to the light-darkness cycle. Epidemiologic studies have implicated circadian disruption in the development of br ... Full text Link to item Cite

The phosphorylation switch that regulates ticking of the circadian clock.

Journal Article Mol Cell · March 18, 2021 In our 24/7 well-lit world, it's easy to skip or delay sleep to work, study, and play. However, our circadian rhythms are not easily fooled; the consequences of jet lag and shift work are many and severe, including metabolic, mood, and malignant disorders. ... Full text Link to item Cite

YJ5 as an immunohistochemical marker of osteogenic lineage.

Journal Article Pathology · February 2021 Overexpression of WLS, an upstream protein in the Wnt pathway, has been implicated in several non-osteogenic tumours. This study represents the first attempt at evaluating WLS expression in various bone and soft tissue tumours using YJ5, a monoclonal antib ... Full text Link to item Cite

Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway.

Journal Article Cancer Res · January 15, 2021 Aberrant Wnt signaling drives a number of cancers through regulation of diverse downstream pathways. Wnt/β-catenin signaling achieves this in part by increasing the expression of proto-oncogenes such as MYC and cyclins. However, global assessment of the Wn ... Full text Link to item Cite

Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion.

Journal Article Cell · January 7, 2021 Wnts are evolutionarily conserved ligands that signal at short range to regulate morphogenesis, cell fate, and stem cell renewal. The first and essential steps in Wnt secretion are their O-palmitoleation and subsequent loading onto the dedicated transporte ... Full text Link to item Cite

Hematopoietic Wnts Modulate Endochondral Ossification During Fracture Healing.

Journal Article Frontiers in endocrinology · January 2021 Wnt signaling plays a critical role in bone formation, homeostasis, and injury repair. Multiple cell types in bone have been proposed to produce the Wnts required for these processes. The specific role of Wnts produced from cells of hematopoietic origin ha ... Full text Cite

Structural model of PORCN illuminates disease-associated variants and drug binding sites

Journal Article · 2021 ABSTRACT Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, a ... Full text Cite

The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition.

Journal Article Cancer Res · December 15, 2020 A subset of Wnt-addicted cancers are sensitive to targeted therapies that block Wnt secretion or receptor engagement. RNF43 loss-of-function (LOF) mutations that increase cell surface Wnt receptor abundance cause sensitivity to Wnt inhibitors. However, it ... Full text Link to item Cite

Wnt-regulated lncRNA discovery enhanced by in vivo identification and CRISPRi functional validation.

Journal Article Genome Med · October 22, 2020 BACKGROUND: Wnt signaling is an evolutionarily conserved developmental pathway that is frequently hyperactivated in cancer. While multiple protein-coding genes regulated by Wnt signaling are known, the functional lncRNAs regulated by Wnt signaling have not ... Full text Link to item Cite

Wnts and the hallmarks of cancer.

Journal Article Cancer Metastasis Rev · September 2020 Since the discovery of the first mammalian Wnt proto-oncogene in virus-induced mouse mammary tumors almost four decades ago, Wnt signaling pathway and its involvement in cancers have been extensively investigated. Activation of this evolutionarily conserve ... Full text Link to item Cite

Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch.

Journal Article Proc Natl Acad Sci U S A · May 19, 2020 Casein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned wheth ... Full text Link to item Cite

Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch.

Journal Article Elife · February 11, 2020 Post-translational control of PERIOD stability by Casein Kinase 1δ and ε (CK1) plays a key regulatory role in metazoan circadian rhythms. Despite the deep evolutionary conservation of CK1 in eukaryotes, little is known about its regulation and the factors ... Full text Link to item Cite

Wnt Signaling and Drug Resistance in Cancer.

Journal Article Mol Pharmacol · February 2020 Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptor ... Full text Link to item Cite

A Ras-LSD1 axis activates PI3K signaling through PIK3IP1 suppression.

Journal Article Oncogenesis · January 2, 2020 PI3K Interacting Protein 1 (PIK3IP1) is a suppressor of the PI3K/Akt/mTOR pathway. We previously reported that activated Ras suppresses PIK3IP1 expression to positively regulate the PI3K pathway in cancer cells. Using doxycycline-inducible PIK3IP1, here we ... Full text Link to item Cite

Wnt-regulated lncRNA discovery enhanced byin vivoidentification and CRISPRi functional validation

Journal Article · 2020 Background Wnt signaling is an evolutionarily conserved developmental pathway that is frequently hyperactivated in cancer. While multiple protein-coding genes regulated by Wnt signaling are known, the functional lncRNAs regulated by Wnt signaling ... Full text Cite

The functional landscape of patient derived RNF43 mutations predicts Wnt inhibitor sensitivity

Journal Article · 2020 A subset of Wnt-addicted cancers are sensitive to targeted therapies that block Wnt secretion or receptor engagement. RNF43 loss-of-function mutations that increase cell surface Wnt receptor abundance cause sensitivity to Wnt inhibitors. However, it is not ... Full text Cite

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Journal Article · 2020 ABSTRACT Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clin ... Full text Cite

Broad regulation of gene isoform expression by Wnt signaling in cancer.

Journal Article RNA · December 2019 Differential gene isoform expression is a ubiquitous mechanism to enhance proteome diversity and maintain cell homeostasis. Mechanisms such as splicing that drive gene isoform variability are highly dynamic and responsive to changes in cell signaling pathw ... Full text Link to item Cite

Opposing actions of renal tubular- and myeloid-derived porcupine in obstruction-induced kidney fibrosis.

Journal Article Kidney Int · December 2019 Wnt/β-catenin signaling is essential in the pathogenesis of renal fibrosis. We previously reported inhibition of the Wnt O-acyl transferase porcupine, required for Wnt secretion, dramatically attenuates kidney fibrosis in the murine unilateral ureteral obs ... Full text Link to item Cite

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers.

Journal Article Oncogene · October 2019 Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is aggressive and lethal. Although there is an urgent need for effective therapeutics in treating pancreatic cancer, none of the targeted therapies tested in clinical trials to date significantly i ... Full text Link to item Cite

Casein Kinase 1 dynamics underlie the PER2 circadian phosphoswitch

Journal Article · August 14, 2019 Summary Post-translational control of PERIOD stability by Casein Kinase 1δ and ε (CK1) plays a key regulatory role in metazoan circadian rhythms. Despite the deep evolutionary conservation of CK1 in eukaryotes, little is known about its regulation and the ... Full text Cite

Pathogenic mutations in neurofibromin identifies a leucine-rich domain regulating glioma cell invasiveness.

Journal Article Oncogene · July 2019 Glioblastoma (GBM) is the most aggressive tumor of the brain. NF1, a tumor suppressor gene and RAS-GTPase, is one of the highly mutated genes in GBM. Dysregulated NF1 expression promotes cell invasion, proliferation, and tumorigenesis. Loss of NF1 expressi ... Full text Link to item Cite

Stromal control of intestinal development and the stem cell niche.

Journal Article Differentiation · 2019 Intestinal homeostasis is dependent on the continuous production of differentiated epithelial cells from a sustainable and resilient stem cell compartment. Wnt/β-catenin signaling plays a central role in this process, cooperating with R-spondins, growth fa ... Full text Link to item Cite

Wnt traffic from endoplasmic reticulum to filopodia.

Journal Article PLoS One · 2019 Wnts are a family of secreted palmitoleated glycoproteins that play key roles in cell to cell communication during development and regulate stem cell compartments in adults. Wnt receptors, downstream signaling cascades and target pathways have been extensi ... Full text Link to item Cite

Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch

Journal Article · 2019 Casein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned wheth ... Full text Cite

Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis.

Journal Article J Clin Invest · December 3, 2018 Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent si ... Full text Link to item Cite

Foxp1 Is Indispensable for Ductal Morphogenesis and Controls the Exit of Mammary Stem Cells from Quiescence.

Journal Article Dev Cell · December 3, 2018 Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their ... Full text Link to item Cite

Phase I extension study of ETC-159 an oral PORCN inhibitor administered with bone protective treatment, in patients with advanced solid tumours

Conference Annals of oncology : official journal of the European Society for Medical Oncology · November 1, 2018 Full text Cite

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche.

Journal Article Dev Cell · September 24, 2018 The gut absorbs dietary nutrients and provides a barrier to xenobiotics and microbiome metabolites. To cope with toxin exposures, the intestinal epithelium is one of the most rapidly proliferating tissues in the body. The stem cell niche supplies essential ... Full text Link to item Cite

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells.

Journal Article J Clin Invest · August 31, 2018 Intestinal homeostasis depends on a slowly proliferating stem cell compartment in crypt cells, followed by rapid proliferation of committed progenitor cells in the transit amplifying (TA) compartment. The balance between proliferation and differentiation i ... Full text Link to item Cite

Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates.

Journal Article Elife · July 31, 2018 Signaling filopodia, termed cytonemes, are dynamic actin-based membrane structures that regulate the exchange of signaling molecules and their receptors within tissues. However, how cytoneme formation is regulated remains unclear. Here, we show that Wnt/pl ... Full text Link to item Cite

CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch.

Journal Article Proc Natl Acad Sci U S A · June 5, 2018 Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein ... Full text Link to item Cite

Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.

Journal Article Proc Natl Acad Sci U S A · June 5, 2018 The N6-methylation of internal adenosines (m6A) in mRNA has been quantified and localized throughout the transcriptome. However, the physiological significance of m6A in most highly methylated mRNAs is unknown. It was demonstrated previously that the circa ... Full text Link to item Cite

PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo.

Journal Article Proc Natl Acad Sci U S A · April 3, 2018 Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5-expressing intestinal stem ... Full text Link to item Cite

Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis.

Journal Article Oncogene · January 18, 2018 Evasion of forkhead box O (FOXO) family of longevity-related transcription factors-mediated growth suppression is necessary to promote cancer development. Since somatic alterations or mutations and transcriptional dysregulation of the FOXO genes are infreq ... Full text Link to item Cite

Ca2+-dependent demethylation of phosphatase PP2Ac promotes glucose deprivation-induced cell death independently of inhibiting glycolysis.

Journal Article Sci Signal · January 9, 2018 Cancer cells increase glucose metabolism to support aerobic glycolysis. However, only some cancer cells are acutely sensitive to glucose withdrawal, and the underlying mechanism of this selective sensitivity is unclear. We showed that glucose deprivation i ... Full text Link to item Cite

Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.

Journal Article Bone Res · 2018 Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted a ... Full text Link to item Cite

Oncogenic Wnt/STOP signaling regulates ribosome biogenesis in vivo

Journal Article · 2018 Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent si ... Full text Cite

Visualizing Wnt secretion from Endoplasmic Reticulum to Filopodia

Journal Article · 2018 Wnts are a family of secreted palmitoleated glycoproteins that play a key role in cell to cell communications during development and regulate stem cell compartments in adults. Wnt receptors, downstream signaling cascades and target pathways have been exten ... Full text Cite

Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.

Journal Article J Med Chem · August 10, 2017 Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throu ... Full text Link to item Cite

Abstract 1172: In vivo pharmacokinetic properties and antitumor efficacy of porcupine lead inhibitors in the orthotopic murine MMTV-Wnt1 breast tumor model and the human HPAF-II pancreatic xenograft mouse model

Conference Cancer Research · July 1, 2017 AbstractPorcupine (PORCN), a muti-pass integral membrane-bound-O-Acyl acyltransferase (MBOAT), resides in the in the endoplasmic reticulum (ER) and is required for biogenesis of Wnt ligands. The secreted mat ... Full text Cite

First-in-human phase 1 study of ETC-159 an oral PORCN inhbitor in patients with advanced solid tumours.

Conference Journal of Clinical Oncology · May 20, 2017 2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, ... Full text Cite

A Flick of the Tail Keeps the Circadian Clock in Line.

Journal Article Mol Cell · May 18, 2017 Circadian clocks signal and adapt to an ever-changing world by juggling a panoply of transcriptional and post-translational modifications. In this issue of Molecular Cell, Gustafson et al. (2017) report an additional requirement for accurate timekeeping, a ... Full text Link to item Cite

Wnt proteins synergize to activate β-catenin signaling.

Journal Article J Cell Sci · May 1, 2017 Wnt ligands are involved in diverse signaling pathways that are active during development, maintenance of tissue homeostasis and in various disease states. While signaling regulated by individual Wnts has been extensively studied, Wnts are rarely expressed ... Full text Link to item Cite

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock.

Journal Article Front Neurol · 2017 An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body ... Full text Link to item Cite

Site-specific phosphorylation of casein kinase 1 δ (CK1δ) regulates its activity towards the circadian regulator PER2.

Journal Article PLoS One · 2017 Circadian rhythms are intrinsic ~24 hour cycles that regulate diverse aspects of physiology, and in turn are regulated by interactions with the external environment. Casein kinase 1 delta (CK1δ, CSNK1D) is a key regulator of the clock, phosphorylating both ... Full text Link to item Cite

CK1δ: a pharmacologically tractable Achilles' heel of Wnt-driven cancers?

Journal Article Ann Transl Med · November 2016 Aberrant Wnt signaling has been widely accepted to be a key driver of a subset of human cancers and a heavily scrutinized molecular pathway for the development of personalized medicine. In a recently published issue of Science Translational Medicine, Rosen ... Full text Link to item Cite

Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.

Journal Article Stem Cells · October 2016 In most human somatic cells, the lack of telomerase activity results in progressive telomere shortening during each cell division. Eventually, DNA damage responses triggered by critically short telomeres induce an irreversible cell cycle arrest termed repl ... Full text Link to item Cite

Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways.

Journal Article Oncogene · August 18, 2016 The cascade that culminates in macrometastases is thought to be mediated by phenotypic plasticity, including epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET). Although there is substantial support for the role of EMT in driving c ... Full text Open Access Link to item Cite

Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization.

Journal Article Protein Cell · July 2016 Protein phosphatase 2A (PP2A) accounts for the majority of total Ser/Thr phosphatase activities in most cell types and regulates many biological processes. PP2A holoenzymes contain a scaffold A subunit, a catalytic C subunit, and one of the regulatory/targ ... Full text Link to item Cite

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.

Journal Article Proc Natl Acad Sci U S A · May 24, 2016 The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Fri ... Full text Link to item Cite

Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.

Journal Article Kidney Int · May 2016 Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, b ... Full text Open Access Link to item Cite

Keeping autophagy in cheCK1.

Journal Article Mol Cell Oncol · May 2016 Mutant RAS-driven cancer cells cope with proliferative stress by increasing basal autophagy to maintain protein/organelle and energy homeostasis. We recently demonstrated that casein kinase 1 alpha (CK1α), a therapeutically tractable enzyme, is critical fo ... Full text Link to item Cite

Wnt addiction of genetically defined cancers reversed by PORCN inhibition.

Journal Article Oncogene · April 28, 2016 Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secre ... Full text Link to item Cite

NOTUM is a potential pharmacodynamic biomarker of Wnt pathway inhibition.

Journal Article Oncotarget · March 15, 2016 Activation of Wnt signaling due to Wnt overexpression or mutations of Wnt pathway components is associated with various cancers. Blocking Wnt secretion by inhibiting PORCN enzymatic activity has shown efficacy in a subset of cancers with elevated Wnt signa ... Full text Link to item Cite

Scaffold hopping and optimization of maleimide based porcupine inhibitors

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · March 13, 2016 Link to item Cite

Abstract P4-08-03: DEAD-box RNA helicase DP103 as a novel regulator of Wnt/β-catenin signaling pathway and promotes cancer stem cell-like behavior in triple negative breast cancers

Conference Cancer Research · February 15, 2016 AbstractDespite recent advances in breast cancer therapeutics, mortality of metastatic triple negative breast cancer (TNBC) subtype remains high; due to their lack of hormone receptors expression for targete ... Full text Cite

Abstract A30: Frizzled-7 (FZD7)-mediated non-canonical Wnt-Planar Cell Polarity (PCP) signalling pathway as a novel molecular driver for the C5/Proliferative/Stem-A molecular subtype of ovarian cancer.

Conference Clinical Cancer Research · January 15, 2016 AbstractOvarian cancer (OC), in particular high grade serous carcinoma (HGSC), has been shown to exhibit diverse molecular heterogeneity based on gene expression profiling by the Australian and the TCGA coho ... Full text Cite

Wnt inhibition enhances browning of mouse primary white adipocytes.

Journal Article Adipocyte · 2016 The global epidemic in obesity and metabolic syndrome requires novel approaches to tackle. White adipose tissue, traditionally seen as a passive energy-storage organ, can be induced to take on certain characteristics of brown fat in a process called browni ... Full text Link to item Cite

Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.

Journal Article Oncotarget · October 20, 2015 The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). ... Full text Link to item Cite

A Period2 Phosphoswitch Regulates and Temperature Compensates Circadian Period.

Journal Article Mol Cell · October 1, 2015 Period (PER) protein phosphorylation is a critical regulator of circadian period, yet an integrated understanding of the role and interaction between phosphorylation sites that can both increase and decrease PER2 stability remains elusive. Here, we propose ... Full text Link to item Cite

Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells.

Journal Article Blood · August 27, 2015 Wnt signaling controls early embryonic hematopoiesis and dysregulated β-catenin is implicated in leukemia. However, the role of Wnts and their source in adult hematopoiesis is still unclear, and is clinically important as upstream Wnt inhibitors enter clin ... Full text Link to item Cite

Discovery and Optimization of a Porcupine Inhibitor.

Journal Article J Med Chem · August 13, 2015 Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates ... Full text Link to item Cite

Abstract 4449: A novel Porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations

Conference Cancer Research · August 1, 2015 AbstractVarious mutations in the Wnt pathway contribute to aberrant activation of Wnt signaling, which is implicated in multiple cancers. Besides the mutation of Adenomatous polyposis coli (APC) or beta-cate ... Full text Cite

Targeting Wnts at the source--new mechanisms, new biomarkers, new drugs.

Journal Article Mol Cancer Ther · May 2015 Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of β-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactio ... Full text Link to item Cite

TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

Journal Article Oncotarget · April 10, 2015 Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a ... Full text Link to item Cite

Casein kinase 1α-dependent feedback loop controls autophagy in RAS-driven cancers.

Journal Article J Clin Invest · April 2015 Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target. RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses. Here we rep ... Full text Link to item Cite

Moving upstream in the war on WNTs.

Journal Article J Clin Invest · March 2, 2015 Cholangiocarcinoma is a relatively rare cancer of the biliary ducts that is highly refractory to treatment. The factors that drive cholangiocarcinoma are poorly understood, though chronic liver fluke infection is a risk factor for disease. In this issue of ... Full text Link to item Cite

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression.

Journal Article Mod Pathol · March 2015 The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aber ... Full text Link to item Cite

Casein kinase 1 regulates Sprouty2 in FGF-ERK signaling.

Journal Article Oncogene · January 22, 2015 Sprouty2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase signaling, and is implicated as a tumor suppressor. SPRY2 inhibits FGF-RAS-ERK signaling by binding to growth factor receptor bound protein 2 (GRB2) during fibroblast growth factor ... Full text Link to item Cite

B56-PP2A regulates motor dynamics for mitotic chromosome alignment.

Journal Article J Cell Sci · November 1, 2014 Proper alignment of duplicated chromosomes at the metaphase plate involves both motor-driven chromosome movement and the functional and physical end-on connection (K-fiber formation) between the kinetochore and the plus-end of microtubules. The B56 family ... Full text Link to item Cite

Updating the Wnt pathways.

Journal Article Biosci Rep · October 17, 2014 In the three decades since the discovery of the Wnt1 proto-oncogene in virus-induced mouse mammary tumours, our understanding of the signalling pathways that are regulated by the Wnt proteins has progressively expanded. Wnts are involved in an complex sign ... Full text Link to item Cite

Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity.

Journal Article Blood · October 2, 2014 Bcl-2 is frequently overexpressed in hematopoietic malignancies, and selective phosphorylation at ser70 enhances its antiapoptotic activity. Phospho-ser70 is dephosphorylated by specific heterotrimers of protein phosphatase 2A (PP2A). We report here that a ... Full text Link to item Cite

FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway.

Journal Article Cell Death Dis · July 17, 2014 Ovarian cancer (OC) can be classified into five biologically distinct molecular subgroups: epithelial-A (Epi-A), Epi-B, mesenchymal (Mes), Stem-A and Stem-B. Among them, Stem-A expresses genes relating to stemness and is correlated with poor clinical progn ... Full text Link to item Cite

Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.

Journal Article J Clin Invest · July 2014 The number of newly formed neurons declines rapidly during aging, and this decrease in neurogenesis is associated with decreased function of neural stem/progenitor cells (NPCs). Here, we determined that a WIP1-dependent pathway regulates NPC differentiatio ... Full text Link to item Cite

Disulfide bond requirements for active Wnt ligands.

Journal Article J Biol Chem · June 27, 2014 Secreted Wnt lipoproteins are cysteine-rich and lipid-modified morphogens that bind to the Frizzled (FZD) receptor and LDL receptor-related protein 6 (LRP6). Wnt engages FZD through protruding thumb and index finger domains, which are each assembled from p ... Full text Link to item Cite

Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts.

Journal Article Development · June 2014 Wnt/β-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth cells as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intes ... Full text Link to item Cite

WLS retrograde transport to the endoplasmic reticulum during Wnt secretion.

Journal Article Dev Cell · May 12, 2014 Wnts are transported to the cell surface by the integral membrane protein WLS (also known as Wntless, Evi, and GPR177). Previous studies of WLS trafficking have emphasized WLS movement from the Golgi to the plasma membrane (PM) and then back to the Golgi v ... Full text Link to item Cite

Abstract C248: Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers.

Journal Article Molecular Cancer Therapeutics · November 1, 2013 AbstractDysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from in ... Full text Cite

Unwinding the Wnt action of casein kinase 1.

Journal Article Cell Res · June 2013 The casein kinase 1 (CK1) family, a major intracellular serine/threonine kinase, is implicated in multiple pathways; however, understanding its regulation has proven challenging. A recent study published in Science identifying allosteric activation of CK1 ... Full text Link to item Cite

BUBR1 recruits PP2A via the B56 family of targeting subunits to promote chromosome congression.

Journal Article Biol Open · May 15, 2013 BUBR1 is a mitotic phosphoprotein essential for the maintenance of chromosome stability by promoting chromosome congression and proper kinetochore-microtubule (K-fiber) attachment, but the underlying mechanism(s) has remained elusive. Here we identify BUBR ... Full text Open Access Link to item Cite

Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer.

Journal Article Cancer Res · January 15, 2013 Porcupine (PORCN) is a membrane bound O-acyltransferase that is required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN for their activity, suggesting that inhibition of PORCN could be an effective treatmen ... Full text Link to item Cite

172 Identification of Small Molecule Inhibitors of Wnt Secretion

Conference European Journal of Cancer · November 2012 Full text Cite

Precise regulation of porcupine activity is required for physiological Wnt signaling.

Journal Article J Biol Chem · October 5, 2012 Gradients of diverse Wnt proteins regulate development, renewal, and differentiation. Porcupine (PORCN) is a membrane-bound O-acyltransferase that is required for post-translational modification of all Wnts to enable their transport, secretion, and activit ... Full text Link to item Cite

A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities.

Journal Article Differentiation · September 2012 Wnt ligands are secreted morphogens that control multiple developmental processes during embryogenesis and adult homeostasis. A diverse set of receptors and signals have been linked to individual Wnts, but the lack of tools for comparative analysis has lim ... Full text Link to item Cite

Modulation of Wnt/β-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer.

Journal Article Oncogene · January 12, 2012 Using a screen for Wnt/β-catenin inhibitors, a family of 8-hydroxyquinolone derivatives with in vivo anti-cancer properties was identified. Analysis of microarray data for the lead compound N-((8-hydroxy-7-quinolinyl) (4-methylphenyl)methyl)benzamide (HQBA ... Full text Link to item Cite

PORCN moonlights in a Wnt-independent pathway that regulates cancer cell proliferation.

Journal Article PLoS One · 2012 Porcupine (PORCN) is a membrane-bound O-acyl transferase that is required for the palmitoylation of Wnt proteins, and that is essential in diverse Wnt pathways for Wnt-Wntless (WLS) binding, Wnt secretion, and Wnt signaling activity. We tested if PORCN was ... Full text Link to item Cite

A densely interconnected genome-wide network of microRNAs and oncogenic pathways revealed using gene expression signatures.

Journal Article PLoS Genet · December 2011 MicroRNAs (miRNAs) are important components of cellular signaling pathways, acting either as pathway regulators or pathway targets. Currently, only a limited number of miRNAs have been functionally linked to specific signaling pathways. Here, we explored i ... Full text Link to item Cite

IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1δ/ɛ and Wnt/β-catenin independent inhibition of mitotic spindle formation.

Journal Article Oncogene · June 2, 2011 Casein kinase 1 delta and epsilon (CK1δ/ɛ) are key regulators of diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. Recent studies suggest that they have an important role in oncogenesis. RNA interfere ... Full text Link to item Cite

Casein kinase 1: Complexity in the family.

Journal Article Int J Biochem Cell Biol · April 2011 The CK1 family of serine/threonine kinases regulates diverse cellular processes, through binding to and phosphorylation a myriad of protein substrates. CK1 prefers substrates primed by prior phosphorylation, and works closely with other kinases in the Wnt ... Full text Link to item Cite

Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.

Journal Article PLoS One · October 21, 2010 PTEN, a phosphoinositide-3-phosphatase, serves dual roles as a tumor suppressor and regulator of cellular anabolic/catabolic metabolism. Adaptation of a redox-sensitive cysteinyl thiol in PTEN for signal transduction by hydrogen peroxide may have superimpo ... Full text Link to item Cite

WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification.

Journal Article J Cell Sci · October 1, 2010 Wnt proteins are secreted post-translationally modified proteins that signal locally to regulate development and proliferation. The production of bioactive Wnts requires a number of dedicated factors in the secreting cell whose coordinated functions are no ... Full text Link to item Cite

Abstract B264: IC261 induces cell cycle arrest and apoptosis of human cancer cells via a CK1δ/ε independent mechanism

Conference Molecular Cancer Therapeutics · December 10, 2009 AbstractCasein kinase 1 delta (CK1δ) and CK1 epsilon (CK1ε) regulate Wnt/β catenin signaling and their dysregulation has been implicated in a variety of human cancers. Kinome RNAi screens and as well as targ ... Full text Cite

Carteriosulfonic acids A-C, GSK-3beta inhibitors from a Carteriospongia sp.

Journal Article J Nat Prod · September 2009 Modulators of Wnt signaling have therapeutic potential in a number of human diseases. A fractionated library from marine invertebrates was screened in a luciferase assay designed to identify modulators of Wnt signaling. A fraction from a Carteriospongia sp ... Full text Link to item Cite

Protein phosphatase 2A regulates self-renewal of Drosophila neural stem cells.

Journal Article Development · July 2009 Drosophila larval brain neural stem cells, also known as neuroblasts, divide asymmetrically to generate a self-renewing neuroblast and a ganglion mother cell (GMC) that divides terminally to produce two differentiated neurons or glia. Failure of asymmetric ... Full text Link to item Cite

Keeping the beat in the rising heat.

Journal Article Cell · May 15, 2009 Circadian clocks use temperature compensation to keep accurate time over a range of temperatures, thus allowing reliable timekeeping under diverse environmental conditions. Mehra et al. (2009) and Baker et al. (2009) now show that phosphorylation-regulated ... Full text Link to item Cite

Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives.

Journal Article Bioorg Med Chem · March 15, 2009 The Wnt signaling pathway regulates cell growth and development in metazoans, and is therefore of interest for drug discovery. By screening a library of 5808 pre-fractionated marine extracts in a cell-based Wnt signaling assay, several signaling activators ... Full text Link to item Cite

From promiscuity to precision: protein phosphatases get a makeover.

Journal Article Mol Cell · March 13, 2009 The control of biological events requires strict regulation using complex protein phosphorylation and dephosphorylation strategies. The bulk of serine-threonine dephosphorylations are catalyzed by a handful of phosphatase catalytic subunits, giving rise to ... Full text Link to item Cite

Wnt signaling in development, disease and translational medicine.

Journal Article Curr Drug Targets · July 2008 Wnt signaling regulates a multitude of critical processes in development and tissue homeostasis. The wingless (wg) gene product was first identified in Drosophila in 1973. Subsequently, the proto-oncogene INT-1 was identified in mice in 1984 when its activ ... Full text Link to item Cite

Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins.

Journal Article Neuron · April 10, 2008 The intrinsic period of circadian clocks is their defining adaptive property. To identify the biochemical mechanisms whereby casein kinase1 (CK1) determines circadian period in mammals, we created mouse null and tau mutants of Ck1 epsilon. Circadian period ... Full text Link to item Cite

Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1.

Journal Article Proc Natl Acad Sci U S A · December 11, 2007 Inactivation of maturation-promoting factor [(MPF) Cdk1/Cyclin B] is a key event in the exit from mitosis. Although degradation of Cyclin B is important for MPF inactivation, recent studies indicate that Cdk1 phosphorylation and inactivation occur before C ... Full text Link to item Cite

After hours keeps clock researchers CRYing Overtime.

Journal Article Cell · June 1, 2007 Three recent reports, including one in this issue of Cell, reveal that the circadian regulator CRY is targeted for degradation by the F box E3 ubiquitin ligase FBXL3 (Siepka et al., 2007; Busino et al., 2007; Godinho et al., 2007). These studies confirm th ... Full text Link to item Cite

Beyond intuitive modeling: combining biophysical models with innovative experiments to move the circadian clock field forward.

Journal Article J Biol Rhythms · June 2007 Two major approaches have been used to model circadian clocks. Qualitative modeling, used prior to the recent wealth of detailed molecular knowledge, makes general predictions but cannot provide detailed mechanistic insights. The more recent biophysical ap ... Full text Link to item Cite

Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex.

Journal Article EMBO J · March 21, 2007 Featured Publication The Wnt/beta-catenin signaling pathway is critical in both cellular proliferation and organismal development. However, how the beta-catenin degradation complex is inhibited upon Wnt activation remains unclear. Using a directed RNAi screen we find that prot ... Full text Link to item Cite

Disease-associated casein kinase I delta mutation may promote adenomatous polyps formation via a Wnt/beta-catenin independent mechanism.

Journal Article Int J Cancer · March 1, 2007 The Wnt signaling pathway is critical for embryonic development and is dysregulated in multiple cancers. Two closely related isoforms of casein kinase I (CKIdelta and epsilon) are positive regulators of this pathway. We speculated that mutations in the aut ... Full text Link to item Cite

A Wnt-CKIvarepsilon-Rap1 pathway regulates gastrulation by modulating SIPA1L1, a Rap GTPase activating protein.

Journal Article Dev Cell · March 2007 Featured Publication Noncanonical Wnt signals control morphogenetic movements during vertebrate gastrulation. Casein kinase I epsilon (CKIvarepsilon) is a Wnt-regulated kinase that regulates Wnt/beta-catenin signaling and has a beta-catenin-independent role(s) in morphogenesis ... Full text Link to item Cite

Post-translational modifications regulate the ticking of the circadian clock.

Journal Article Nat Rev Mol Cell Biol · February 2007 Featured Publication Getting a good night's sleep is on everyone's to-do list. So is, no doubt, staying awake during late afternoon seminars. Our internal clocks control these and many more workings of the body, and disruptions of the circadian clocks predispose individuals to ... Full text Link to item Cite

Differential expression of the B'beta regulatory subunit of protein phosphatase 2A modulates tyrosine hydroxylase phosphorylation and catecholamine synthesis.

Journal Article J Biol Chem · January 5, 2007 Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, is stimulated by N-terminal phosphorylation by several kinases and inhibited by protein serine/threonine phosphatase 2A (PP2A). PP2A is a family of heterotrimeric holoenzymes c ... Full text Link to item Cite

Reversible protein phosphorylation regulates circadian rhythms.

Journal Article Cold Spring Harb Symp Quant Biol · 2007 Protein phosphorylation regulates the period of the circadian clock within mammalian cells. Circadian rhythms are an approximately 24-hour cycle that regulates key biological processes. Daily fluctuations of wakefulness, stress hormones, lipid metabolism, ... Full text Link to item Cite

Role for the PP2A/B56delta phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis.

Journal Article Cell · November 17, 2006 Featured Publication DNA-responsive checkpoints prevent cell-cycle progression following DNA damage or replication inhibition. The mitotic activator Cdc25 is suppressed by checkpoints through inhibitory phosphorylation at Ser287 (Xenopus numbering) and docking of 14-3-3. Ser28 ... Full text Link to item Cite

Protein phosphatase 1 regulates the stability of the circadian protein PER2.

Journal Article Biochem J · October 1, 2006 Featured Publication The circadian clock is regulated by a transcription/translation negative feedback loop. A key negative regulator of circadian rhythm in mammals is the PER2 (mammalian PERIOD 2) protein. Its daily degradation at the end of the night accompanies de-repressio ... Full text Link to item Cite

Site-specific casein kinase 1epsilon-dependent phosphorylation of Dishevelled modulates beta-catenin signaling.

Journal Article FEBS J · October 2006 Careful regulation of the Wnt-Beta-catenin signaling pathway is critical to many aspects of development and cancer. Casein kinase Iepsilon is a Wnt-activated positive regulator of this pathway. Members of the Dishevelled family have been identified as key ... Full text Link to item Cite

An opposite role for tau in circadian rhythms revealed by mathematical modeling.

Journal Article Proc Natl Acad Sci U S A · July 11, 2006 Featured Publication Biological clocks with a period of approximately 24 h (circadian) exist in most organisms and time a variety of functions, including sleep-wake cycles, hormone release, bioluminescence, and core body temperature fluctuations. Much of our understanding of t ... Full text Link to item Cite

Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation.

Journal Article J Biol Chem · May 5, 2006 Featured Publication Wnt signaling acts in part through the low density lipoprotein receptor-related transmembrane proteins LRP5 and LRP6 to regulate embryonic development and stem cell proliferation. Up-regulated signaling is associated with many forms of cancer. Casein kinas ... Full text Link to item Cite

Protein serine/threonine phosphatases: life, death, and sleeping.

Journal Article Curr Opin Cell Biol · April 2005 Featured Publication Protein serine/threonine phosphatases control key biological pathways including early embryonic development, cell proliferation, cell death, circadian rhythm and cancer. Recent studies have provided important insights into how several of the many phosphata ... Full text Link to item Cite

Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation.

Journal Article Mol Cell Biol · April 2005 Featured Publication The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function o ... Full text Link to item Cite

Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities.

Journal Article Nat Genet · April 2005 Autosomal dominant mutations in the gene encoding the basic helix-loop-helix transcription factor Twist1 are associated with limb and craniofacial defects in humans with Saethre-Chotzen syndrome. The molecular mechanism underlying these phenotypes is poorl ... Full text Link to item Cite

Casein kinase I in the mammalian circadian clock.

Journal Article Methods Enzymol · 2005 The circadian clock is characterized by daily fluctuations in gene expression, protein abundance, and posttranslational modification of regulatory proteins. The Drosophila PERIOD (dPER) protein is phosphorylated by the serine?threonine protein kinase, DOUB ... Full text Link to item Cite

A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1.

Journal Article Mol Cell Biol · May 2004 In resting cells, the NFAT1 transcription factor is kept inactive in the cytoplasm by phosphorylation on multiple serine residues. These phosphorylated residues are primarily contained within two types of serine-rich motifs, the SRR-1 and SP motifs, which ... Full text Link to item Cite

Regulation of casein kinase I epsilon activity by Wnt signaling.

Journal Article J Biol Chem · March 26, 2004 Featured Publication The Wnt/beta-catenin signaling pathway is important in both development and cancer. Casein kinase Iepsilon (CKIepsilon) is a positive regulator of the canonical Wnt pathway. CKIepsilon itself can be regulated in vitro by inhibitory autophosphorylation, and ... Full text Link to item Cite

Phosphopeptide mapping of proteins ectopically expressed in tissue culture cell lines.

Journal Article Biol Proced Online · 2004 Post-translational modifications such as phosphorylation play a vital role in the regulation of protein function. In our study of the basic Helix-loop-Helix (bHLH) transcription factor HAND1, it was suspected that HAND1 was being phosphorylated during trop ... Full text Link to item Cite

PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation.

Journal Article Mol Cell · November 2003 Featured Publication The bHLH factors HAND1 and HAND2 are required for heart, vascular, neuronal, limb, and extraembryonic development. Unlike most bHLH proteins, HAND factors exhibit promiscuous dimerization properties. We report that phosphorylation/dephosphorylation via PKA ... Full text Link to item Cite

Mechanism of regulation of casein kinase I activity by group I metabotropic glutamate receptors.

Journal Article J Biol Chem · November 22, 2002 Previously, we reported that (S)-3,5-dihydroxypenylglycine (DHPG), an agonist for group I metabotropic glutamate receptors (mGluRs), stimulates CK1 and Cdk5 kinase activities in neostriatal neurons, leading to enhanced phosphorylation, respectively, of Ser ... Full text Link to item Cite

Regulation of BRCA1 phosphorylation by interaction with protein phosphatase 1alpha.

Journal Article Cancer Res · November 15, 2002 Numerous reports have revealed that the tumor suppressor BRCA1 may play an important role in DNA damage repair. BRCA1 is expressed and phosphorylated during cell cycle progression and after DNA damage. BRCA1 is hypophosphorylated in G0-G1 and probably duri ... Link to item Cite

The nucleophosmin-anaplastic lymphoma kinase fusion protein induces c-Myc expression in pediatric anaplastic large cell lymphomas.

Journal Article Am J Pathol · September 2002 The majority of pediatric anaplastic large cell lymphomas (ALCLs) carry the t(2;5)(p23;q35) chromosomal translocation that juxtaposes the dimerization domain of nucleophosmin with anaplastic lymphoma kinase (ALK). The nucleophosmin-ALK fusion induces const ... Full text Link to item Cite

B56-associated protein phosphatase 2A is required for survival and protects from apoptosis in Drosophila melanogaster.

Journal Article Mol Cell Biol · June 2002 Featured Publication Protein phosphorylation and specific protein kinases can initiate signal transduction pathways leading to programmed cell death. The specific protein phosphatases regulating apoptosis have been more elusive. Using double-stranded RNA-mediated interference ... Full text Link to item Cite

The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon.

Journal Article J Biol Chem · May 10, 2002 The serine/threonine protein kinase casein kinase I epsilon (CKIepsilon) is a key regulator of metazoan circadian rhythm. Genetic and biochemical data suggest that CKIepsilon binds to and phosphorylates the PERIOD proteins. However, the PERIOD proteins int ... Full text Link to item Cite

Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex.

Journal Article Proc Natl Acad Sci U S A · February 5, 2002 Featured Publication Wnt signaling plays a key role in cell proliferation and development. Recently, casein kinase I (CKI) and protein phosphatase 2A (PP2A) have emerged as positive and negative regulators of the Wnt pathway, respectively. However, it is not clear how these tw ... Full text Link to item Cite

Casein Kinase

Journal Article · January 15, 2002 Full text Cite

Two conserved domains in regulatory B subunits mediate binding to the A subunit of protein phosphatase 2A.

Journal Article Eur J Biochem · January 2002 Protein phosphatase 2A (PP2A) is an abundant heterotrimeric serine/threonine phosphatase containing highly conserved structural (A) and catalytic (C) subunits. Its diverse functions in the cell are determined by its association with a highly variable regul ... Full text Link to item Cite

Lineage-specific trisomy 21 in a neonate with resolving transient myeloproliferative syndrome.

Journal Article J Pediatr Hematol Oncol · 2002 The cellular events that lead to transient myeloproliferative syndrome (TMS) in patients with trisomy 21 mosaicism confined to the hematopoietic system are poorly understood. The authors attempt to define the event that led to the development of TMS in a s ... Full text Link to item Cite

Nuclear export of mammalian PERIOD proteins.

Journal Article J Biol Chem · December 7, 2001 The timing of mammalian circadian rhythm is determined by interlocking negative and positive transcriptional feedback loops that govern the cyclic expression of both clock regulators and output genes. In mammals, nuclear localization of the circadian regul ... Full text Link to item Cite

An hPer2 phosphorylation site mutation in familial Advanced Sleep-Phase Syndrome.

Conference AMERICAN JOURNAL OF HUMAN GENETICS · October 1, 2001 Link to item Cite

Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus.

Journal Article EMBO J · August 1, 2001 Featured Publication Wnt signaling increases beta-catenin abundance and transcription of Wnt-responsive genes. Our previous work suggested that the B56 regulatory subunit of protein phosphatase 2A (PP2A) inhibits Wnt signaling. Okadaic acid (a phosphatase inhibitor) increases, ... Full text Link to item Cite

Casein kinase I: another cog in the circadian clockworks.

Journal Article Chronobiol Int · May 2001 Multiple components of the circadian central clock are phosphoproteins, and it has become increasingly clear that posttranslational modification is an important regulator of circadian rhythm in diverse organisms, from dinoflagellates to humans. Genetic stu ... Full text Link to item Cite

An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome.

Journal Article Science · February 9, 2001 Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene ... Full text Link to item Cite

Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2.

Journal Article FEBS Lett · February 2, 2001 Casein kinase Iepsilon (CKIepsilon), a central component of the circadian clock, interacts with and phosphorylates human period protein 1 (hPER1) [Keesler, G.A. et al. (2000) NeuroReport 5, 951-955]. A mutation in CKIepsilon causes a shortened circadian pe ... Full text Link to item Cite

Public funding of understanding nature.

Journal Article IUBMB Life · February 2001 Full text Link to item Cite

Pediatric ALK-positive lymphomas coexpress c-Myc.

Journal Article BLOOD · November 16, 2000 Link to item Cite

Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon.

Journal Article Mol Cell Biol · July 2000 Featured Publication The molecular oscillator that keeps circadian time is generated by a negative feedback loop. Nuclear entry of circadian regulatory proteins that inhibit transcription from E-box-containing promoters appears to be a critical component of this loop in both D ... Full text Link to item Cite

Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon.

Journal Article Neuroreport · April 7, 2000 Period (PER), a central component of the circadian clock in Drosophila, undergoes daily oscillation in abundance and phosphorylation state. Here we report that human casein kinase I epsilon (hCKI epsilon) can phosphorylate human PER I (hPER I). Purified re ... Full text Link to item Cite

Protein phosphatase 2A: a panoply of enzymes.

Journal Article Curr Opin Cell Biol · April 2000 Featured Publication Protein phosphatase 2A describes an extended family of intracellular protein serine/threonine phosphatases sharing a common catalytic subunit that regulates a variety of processes by means of diverse regulatory subunits. During the past year, studies have ... Full text Link to item Cite

Identification of casein kinase I substrates by in vitro expression cloning screening.

Journal Article Biochem Biophys Res Commun · February 16, 2000 Casein kinase I (CKI) is a widely expressed protein kinase family implicated in diverse processes including membrane trafficking, DNA repair, and circadian rhythm. Despite the large number of CKI genes, few biologically relevant substrates have been identi ... Full text Link to item Cite

Identification of inhibitory autophosphorylation sites in casein kinase I epsilon.

Journal Article J Biol Chem · November 5, 1999 Casein kinase I epsilon (CKIepsilon) is a widely expressed protein kinase implicated in the regulation of diverse cellular processes including DNA replication and repair, nuclear trafficking, and circadian rhythm. CKIepsilon and the closely related CKIdelt ... Full text Link to item Cite

Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A.

Journal Article Science · March 26, 1999 Featured Publication Dysregulation of Wnt-beta-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies. The adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3beta form a Wnt-regulated signaling compl ... Full text Link to item Cite

Regulation of casein kinase I epsilon and casein kinase I delta by an in vivo futile phosphorylation cycle.

Journal Article J Biol Chem · June 26, 1998 Casein kinase I delta (CKIdelta) and casein kinase I epsilon (CKIepsilon) have been implicated in the response to DNA damage, but the understanding of how these kinases are regulated remains incomplete. In vitro, these kinases rapidly autophosphorylate, pr ... Full text Link to item Cite

Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two-locus model for the etiology of familial tumors.

Journal Article Cancer Res · April 1, 1998 Familial predisposition to Wilms' tumor (WT), a childhood kidney tumor, is inherited as an autosomal dominant trait. For most WT families studied, the 11p13 gene WT1 and genomic regions implicated in tumorigenesis in a subset of tumors can be ruled out as ... Link to item Cite

Autoinhibition of casein kinase I epsilon (CKI epsilon) is relieved by protein phosphatases and limited proteolysis.

Journal Article J Biol Chem · January 16, 1998 Casein kinase I epsilon (CKI epsilon) is a member of the CKI gene family, members of which are involved in the control of SV40 DNA replication, DNA repair, and cell metabolism. The mechanisms that regulate CKI epsilon activity and substrate specificity are ... Full text Link to item Cite

Determinants of casein kinase i epsilon (ckir) autoinhibition

Journal Article FASEB Journal · December 1, 1997 Casein kinase I (CKI) is a rnonomeric, serine/threonine protein kinase that is known to participate in aspects of I")NA metabolism including repair and replication. Many isoforrns of CKI are known to exist in a number of organisms, and splice variants add ... Cite

Regulation of casein kinase i

Journal Article FASEB Journal · December 1, 1997 Casein kinase I ( (CKIf) is a member of (he CKI gene family, members of which are involved in the control of SV40 DNA replication. DNA repair, and cell metabolism. The mechanisms that regulate CKIf activity and substrate specificity are not well understood ... Cite

Regulation of casein kinase I epsilon

Conference FASEB JOURNAL · July 31, 1997 Link to item Cite

The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm.

Journal Article J Biol Chem · September 6, 1996 Protein phosphatase 2A is a heterotrimeric protein serine/threonine phosphatase consisting of a 36-kDa catalytic C subunit, a 65-kDa structural A subunit, and a variable regulatory B subunit. The B subunits determine the substrate specificity of the enzyme ... Full text Link to item Cite

Assignment of human protein phosphatase 2A regulatory subunit genes b56alpha, b56beta, b56gamma, b56delta, and b56epsilon (PPP2R5A-PPP2R5E), highly expressed in muscle and brain, to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2 --> p12.

Journal Article Genomics · August 15, 1996 The activity of the major intracellular protein phosphatase, protein phosphatase 2A (PP2A), is determined by the nature of the associated regulatory subunit. A new family of human PP2A regulatory subunits has recently been identified. Three of these subuni ... Full text Link to item Cite

Identification of a new family of protein phosphatase 2A regulatory subunits.

Journal Article J Biol Chem · November 3, 1995 Protein phosphatase 2A (PP2A) is a major intracellular protein phosphatase that regulates multiple aspects of cell growth and metabolism. The ability of this widely distributed heterotrimeric enzyme to act on a diverse array of substrates is largely contro ... Full text Link to item Cite

Isolation and characterization of human casein kinase I epsilon (CKI), a novel member of the CKI gene family.

Journal Article J Biol Chem · June 23, 1995 The casein kinase I (CKI) gene family is a rapidly enlarging group whose members have been implicated in the control of cytoplasmic and nuclear processes, including DNA replication and repair. We report here the cloning and characterization of a novel isof ... Full text Link to item Cite

Different oligomeric forms of protein phosphatase 2A activate and inhibit simian virus 40 DNA replication.

Journal Article Mol Cell Biol · July 1994 The ability of simian virus 40 (SV40) large T antigen to catalyze the initiation of viral DNA replication is regulated by its phosphorylation state. Previous studies have identified the free catalytic subunit of protein phosphatase 2A (PP2Ac) as the cellul ... Full text Link to item Cite

Enhancing the psychological health of medical students: the student well-being committee.

Journal Article Med Educ · January 1994 Medical schools' emphasis on technical excellence is sometimes at the expense of social and emotional development. This paper describes a programme, orchestrated by a vital Well-Being Committee, that involves students in a wide range of activities to enhan ... Full text Link to item Cite

T-antigen kinase inhibits simian virus 40 DNA replication by phosphorylation of intact T antigen on serines 120 and 123.

Journal Article J Virol · January 1994 Simian virus 40 (SV40) DNA replication begins after two large T-antigen hexamers assemble on the viral minimal origin of replication and locally unwind the template DNA. The activity of T antigen in this reaction is regulated by its phosphorylation state. ... Full text Link to item Cite

Control of simian virus 40 DNA replication by the HeLa cell nuclear kinase casein kinase I.

Journal Article Mol Cell Biol · February 1993 The initiation of simian virus 40 (SV40) DNA replication is regulated by the phosphorylation state of the viral initiator protein, large T antigen. We describe the purification from HeLa cell nuclei of a 35-kDa serine/threonine protein kinase that phosphor ... Full text Link to item Cite

Mechanism of activation of simian virus 40 DNA replication by protein phosphatase 2A.

Journal Article Mol Cell Biol · November 1992 The catalytic subunit of protein phosphatase 2A (PP2Ac) stimulates the initiation of replication of simian virus 40 DNA in vitro by dephosphorylating T antigen at specific phosphoserine residues (K. H. Scheidtmann, D. M. Virshup, and T. J. Kelly, J. Virol. ... Full text Link to item Cite

Focal encephalitis with enterovirus infections.

Journal Article Pediatrics · October 1991 We report on four pediatric patients with Enterovirus infections who were admitted to the hospital with signs or symptoms of acute, focal encephalitis. All four experienced focal seizures. Each had a cerebrospinal fluid pleocytosis at the initial lumbar pu ... Link to item Cite

Protein phosphatase 2A dephosphorylates simian virus 40 large T antigen specifically at residues involved in regulation of DNA-binding activity.

Journal Article J Virol · April 1991 Treatment of purified simian virus 40 large T antigen (LT) with protein phosphatase 2A stimulates LT-dependent DNA unwinding and replication (D. M. Virshup, M. G. Kauffman, and T. J. Kelly, EMBO J. 8: 3891-3898, 1989). The specificity of the catalytic subu ... Full text Link to item Cite

INITIATION OF SV40 DNA-REPLICATION - MECHANISM AND CONTROL

Journal Article COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY · January 1, 1991 Link to item Cite

Initiation of SV40 DNA replication: mechanism and control.

Journal Article Cold Spring Harb Symp Quant Biol · 1991 Full text Link to item Cite

Reconstitution of simian virus 40 DNA replication with purified proteins.

Journal Article Proc Natl Acad Sci U S A · November 1990 Replication of plasmid DNA molecules containing the simian virus 40 (SV40) origin of DNA replication has been reconstituted with seven highly purified cellular proteins plus the SV40 large tumor (T) antigen. Initiation of DNA synthesis is absolutely depend ... Full text Link to item Cite

DNA replication.

Journal Article Curr Opin Cell Biol · June 1990 Full text Link to item Cite

CELLULAR PROTEINS INVOLVED IN SV40 DNA-REPLICATION INVITRO

Conference MOLECULAR MECHANISMS IN DNA REPLICATION AND RECOMBINATION · January 1, 1990 Link to item Cite

Hb Catonsville (glutamic acid inserted between Pro-37(C2)alpha and Thr-38(C3)alpha). Nonallelic gene conversion in the globin system?

Journal Article J Biol Chem · December 25, 1989 Hb Catonsville is an unstable variant in which glutamic acid is inserted into the alpha-globin chain between Pro-37(C2) and Thr-38(C3). The peptide sequence data are consistent with the DNA sequence of the polymerase chain reaction-amplified fragment of th ... Link to item Cite

Activation of SV40 DNA replication in vitro by cellular protein phosphatase 2A.

Journal Article EMBO J · December 1, 1989 We have made use of the cell-free SV40 DNA replication system to identify and characterize cellular proteins required for efficient DNA synthesis. One such protein, replication protein C (RP-C), was shown to be involved with SV40 large T antigen in the ear ... Full text Link to item Cite

Purification of replication protein C, a cellular protein involved in the initial stages of simian virus 40 DNA replication in vitro.

Journal Article Proc Natl Acad Sci U S A · May 1989 The replication of simian virus 40 (SV40) DNA is dependent upon a single viral protein [tumor (T) antigen] and multiple cellular proteins. To define the required cellular proteins, we have made use of a cell-free system that supports the replication of pla ... Full text Link to item Cite

Identification of cellular proteins required for simian virus 40 DNA replication.

Journal Article J Biol Chem · February 15, 1989 Study of the proteins involved in DNA replication of a model system such as SV40 is a first step in understanding eukaryotic chromosomal replication. Using a cell-free system that is capable of replicating plasmid DNA molecules containing the SV40 origin o ... Link to item Cite

Clathrin-coated vesicle assembly polypeptides: physical properties and reconstitution studies with brain membranes.

Journal Article J Cell Biol · January 1988 The assembly polypeptides are an integral component of coated vesicles and may mediate the linkage of clathrin to the vesicle membrane. We have purified assembly polypeptides in milligram quantities from bovine brain by an improved procedure. Hydrodynamic ... Full text Link to item Cite

Cutaneous manifestations of Corynebacterium group JK sepsis.

Journal Article J Am Acad Dermatol · February 1987 A 14-year-old boy developed group JK corynebacteria sepsis and a generalized erythematous macular and papular skin eruption following chemotherapy for relapse of acute lymphocytic leukemia. Lesional skin biopsy demonstrated effacement of eccrine glands by ... Full text Link to item Cite

Bepridil and cetiedil. Vasodilators which inhibit Ca2+-dependent calmodulin interactions with erythrocyte membranes.

Journal Article J Clin Invest · September 1984 Two new vascular smooth muscle relaxants, bepridil and cetiedil, were found to possess specific CaM-inhibitory properties which resembled those of trifluoperazine. Trifluoperazine, bepridil, and cetiedil inhibited Ca2+-dependent 125I-CaM binding to erythro ... Full text Link to item Cite

Unique sensitivity of Hb Zürich to oxidative injury by phenazopyridine: reversal of the effects by elevating carboxyhemoglobin levels in vivo and in vitro.

Journal Article Am J Hematol · June 1983 Phenazopyridine (PAP) causes a hemolytic anemia in normal individuals who receive an overdose or in patients with decreased renal function given therapeutic doses. There are no reports of PAP-induced hemolysis in individuals with unstable hemoglobins. Ther ... Full text Link to item Cite