Mario Gonzalez-Gronow | Scholars@Duke

Mario Gonzalez-Gronow
Associate Professor Emeritus of Pathology

I am primarily involved in studies of the regulation of the plasminogen (Pg) activation system in rheumatoid human synovial fibroblasts relative to endothelial cells, hepatocytes and monocytes. We have found that streptococcal antigens like streptokinase (SK) are able to mimic binding properties of human fibronectin (FN) and thereby have the potential to affect processes on the cell surface involving FN interaction with their normal receptors. Rheumatoid arthritis (RA) in humans is a disease characterized by a chronic autoimmune related inflammatory process focused in the joints leading to a vast destruction of synovial tissue and bone. We have found a correlation between the stage of the disease and the titer of anti-SK antibodies cross-reacting with FN. In addition, we also found that the Pg receptor in RA human synovial fibroblasts has a composition different from that found in normal synovial fibroblasts. We identified the protein components of both normal and RA synovial fibroblasts. These findings led us to postulate a new mechanism which explains the molecular basis for the upregulation of Pg activity on the surface of the rheumatoid inflammed synovium. I am also involved in the study of Pg receptors in prostate cancer cells. I found that the voltage-dependent anion channel (VDAC1) along with the chaperone protein glucose-regulated protein of 78 kDa serve as receptors for Pg. Furthermore, we identified the binding site for alpha-2-macroglobulin in GRP78. This site is the target of autoimmunity in prostate cancer patients who show elevated titers of anti-GRP78 autoantibodies which stimulate tumor cell proliferation. We are presently studying the mechanism by which these autoantibodies protect the tumor cells from apoptosis.

Current Appointments & Affiliations

Associate Professor Emeritus of Pathology, Pathology, Clinical Science Departments 2011

Contact Information

304 Davison Bldg, Durham, NC 27710
Duke Box 3712, Durham, NC 27710
gonza002@mc.duke.edu (919) 684-8879

Background
Education, Training, & Certifications
- D.Sc., University of Chile 1973
- B.S., University of Concepcion (Chile) 1969
Duke Appointment History
- Associate Professor of Pathology, Pathology, Clinical Science Departments 2006 - 2011
- Associate Research Professor of Pathology, Pathology, Clinical Science Departments 2005 - 2006
- Assistant Research Professor of Pathology, Pathology, Clinical Science Departments 1994 - 2005
Research
Selected Grants
- Modulation of Angiogenesis Via the Angiostatin Receptor awarded by National Institutes of Health 2001 - 2007
- Fibrinolysis In Vitro And In Vivo awarded by National Institutes of Health 1995
- Lipoprotein (A), Coagulation And Fibrinolysis awarded by National Institutes of Health 1993 - 1994
- Biosynthesis And Secretion Of Plasminogen awarded by National Institutes of Health 1985 - 1986
Publications & Artistic Works
Selected Publications
- Academic Articles
  - Gonzalez-Gronow, Mario, Jenny L. Fiedler, Cristian Farias Gomez, Fang Wang, Rupa Ray, Paul D. Ferrell, and Salvatore V. Pizzo. “Myelin basic protein stimulates plasminogen activation via tissue plasminogen activator following binding to independent l-lysine-containing domains..” Biochem Biophys Res Commun 490, no. 3 (August 26, 2017): 855–60. https://doi.org/10.1016/j.bbrc.2017.06.131.
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  - Al-Hashimi, Ali A., Jennifer Caldwell, Mario Gonzalez-Gronow, Salvatore V. Pizzo, Danya Aboumrad, Lindsay Pozza, Hiam Al-Bayati, et al. “Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores..” J Biol Chem 290, no. 48 (November 27, 2015). https://doi.org/10.1074/jbc.A110.119107.
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  - Gonzalez-Gronow, Mario, Miguel Cuchacovich, Rina Francos, Stephanie Cuchacovich, Angel Blanco, Rodrigo Sandoval, Cristian Farias Gomez, Javier A. Valenzuela, Rupa Ray, and Salvatore V. Pizzo. “Catalytic autoantibodies against myelin basic protein (MBP) isolated from serum of autistic children impair in vitro models of synaptic plasticity in rat hippocampus..” J Neuroimmunol 287 (October 15, 2015): 1–8. https://doi.org/10.1016/j.jneuroim.2015.07.006.
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  - Gonzalez-Gronow, Mario, Cristian Farias Gomez, Gustaaf G. de Ridder, Rupa Ray, and Salvatore V. Pizzo. “Binding of tissue-type plasminogen activator to the glucose-regulated protein 78 (GRP78) modulates plasminogen activation and promotes human neuroblastoma cell proliferation in vitro..” J Biol Chem 289, no. 36 (September 5, 2014): 25166–76. https://doi.org/10.1074/jbc.M114.589341.
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  - Gonzalez-Gronow, Mario, Rupa Ray, Fang Wang, and Salvatore V. Pizzo. “The voltage-dependent anion channel (VDAC) binds tissue-type plasminogen activator and promotes activation of plasminogen on the cell surface..” J Biol Chem 288, no. 1 (January 4, 2013): 498–509. https://doi.org/10.1074/jbc.M112.412502.
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  - Selim, Maria A., James L. Burchette, Edith V. Bowers, Gustaaf G. de Ridder, Lihong Mo, Salvatore V. Pizzo, and Mario Gonzalez-Gronow. “Changes in oligosaccharide chains of autoantibodies to GRP78 expressed during progression of malignant melanoma stimulate melanoma cell growth and survival..” Melanoma Res 21, no. 4 (August 2011): 323–34. https://doi.org/10.1097/CMR.0b013e3283471042.
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  - Ridder, Gustaaf G. de, Mario Gonzalez-Gronow, Rupa Ray, and Salvatore V. Pizzo. “Autoantibodies against cell surface GRP78 promote tumor growth in a murine model of melanoma..” Melanoma Res 21, no. 1 (February 2011): 35–43. https://doi.org/10.1097/CMR.0b013e3283426805.
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  - Gonzalez-Gronow, Mario, Miguel Cuchacovich, Rina Francos, Stephanie Cuchacovich, Maria del Pilar Fernandez, Angel Blanco, Edith V. Bowers, Steven Kaczowka, and Salvatore V. Pizzo. “Antibodies against the voltage-dependent anion channel (VDAC) and its protective ligand hexokinase-I in children with autism..” J Neuroimmunol 227, no. 1–2 (October 8, 2010): 153–61. https://doi.org/10.1016/j.jneuroim.2010.06.001.
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  - Al-Hashimi, Ali A., Jennifer Caldwell, Mario Gonzalez-Gronow, Salvatore V. Pizzo, Danya Aboumrad, Lindsay Pozza, Hiam Al-Bayati, et al. “Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores..” J Biol Chem 285, no. 37 (September 10, 2010): 28912–23. https://doi.org/10.1074/jbc.M110.119107.
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  - Papalas, John A., Robin T. Vollmer, Mario Gonzalez-Gronow, Salvatore V. Pizzo, James Burchette, Kenneth E. Youens, Krystal B. Johnson, and Maria A. Selim. “Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma..” Mod Pathol 23, no. 1 (January 2010): 134–43. https://doi.org/10.1038/modpathol.2009.152.
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  - Gonzalez-Gronow, Mario, Maria Angelica Selim, John Papalas, and Salvatore V. Pizzo. “GRP78: a multifunctional receptor on the cell surface..” Antioxid Redox Signal 11, no. 9 (September 2009): 2299–2306. https://doi.org/10.1089/ARS.2009.2568.
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  - Gonzalez-Gronow, Mario, Steven Kaczowka, Govind Gawdi, and Salvatore V. Pizzo. “Dipeptidyl peptidase IV (DPP IV/CD26) is a cell-surface plasminogen receptor..” Front Biosci 13 (January 1, 2008): 1610–18.
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  - Papalas, J., J. Turner, J. Burchette, M. Gonzalez-Gronow, and M. Selim. “GRP 78 protein expression in malignant melanoma.” Journal of Cutaneous Pathology 35, no. 1 (January 1, 2008): 135–135.
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  - Gonzalez-Gronow, Mario, Steven J. Kaczowka, Sturgis Payne, Fang Wang, Govind Gawdi, and Salvatore V. Pizzo. “Plasminogen structural domains exhibit different functions when associated with cell surface GRP78 or the voltage-dependent anion channel..” J Biol Chem 282, no. 45 (November 9, 2007): 32811–20. https://doi.org/10.1074/jbc.M703342200.
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  - Gonzalez-Gronow, Mario, Miguel Cuchacovich, Carolina Llanos, Cristian Urzua, Govind Gawdi, and Salvatore V. Pizzo. “Prostate cancer cell proliferation in vitro is modulated by antibodies against glucose-regulated protein 78 isolated from patient serum..” Cancer Res 66, no. 23 (December 1, 2006): 11424–31. https://doi.org/10.1158/0008-5472.CAN-06-1721.
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  - Mavropoulos, John C., Miguel Cuchacovich, Carolina Llanos, Juan C. Aguillón, Hector Gatica, Salvatore V. Pizzo, and Mario Gonzalez-Gronow. “Anti-tumor necrosis factor-alpha therapy augments dipeptidyl peptidase IV activity and decreases autoantibodies to GRP78/BIP and phosphoglucose isomerase in patients with rheumatoid arthritis..” J Rheumatol 32, no. 11 (November 2005): 2116–24.
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  - Wahl, Miriam L., Daniel J. Kenan, Mario Gonzalez-Gronow, and Salvatore V. Pizzo. “Angiostatin's molecular mechanism: aspects of specificity and regulation elucidated..” J Cell Biochem 96, no. 2 (October 1, 2005): 242–61. https://doi.org/10.1002/jcb.20480.
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  - Gonzalez-Gronow, Mario, Uma K. Misra, Govind Gawdi, and Salvatore V. Pizzo. “Association of plasminogen with dipeptidyl peptidase IV and Na+/H+ exchanger isoform NHE3 regulates invasion of human 1-LN prostate tumor cells..” J Biol Chem 280, no. 29 (July 22, 2005): 27173–78. https://doi.org/10.1074/jbc.M500383200.
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  - Cuchacovich, M., G. Merino, J. H. Yamamoto, F. Villarroel, T. Saavedra, S. Jofre, H. Gatica, V. Velasquez, S. V. Pizzo, and M. Gonzalez-Gronow. “Behçet's disease patients present high levels of deglycosylated anti-lipoteichoic acid IgG and high IL-8 production after lipoteichoic acid stimulation..” Clin Exp Rheumatol 23, no. 4 Suppl 38 (July 2005): S27–34.
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  - Misra, Uma Kant, Mario Gonzalez-Gronow, Govind Gawdi, and Salvatore Vincent Pizzo. “The role of MTJ-1 in cell surface translocation of GRP78, a receptor for alpha 2-macroglobulin-dependent signaling..” J Immunol 174, no. 4 (February 15, 2005): 2092–97. https://doi.org/10.4049/jimmunol.174.4.2092.
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  - Gonzalez-Gronow, Mario, Hernan E. Grenett, Govind Gawdi, and Salvatore V. Pizzo. “Angiostatin directly inhibits human prostate tumor cell invasion by blocking plasminogen binding to its cellular receptor, CD26..” Exp Cell Res 303, no. 1 (February 1, 2005): 22–31. https://doi.org/10.1016/j.yexcr.2004.09.008.
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  - Misra, Uma Kant, Mario Gonzalez-Gronow, Govind Gawdi, Fang Wang, and Salvatore Vincent Pizzo. “A novel receptor function for the heat shock protein Grp78: silencing of Grp78 gene expression attenuates alpha2M*-induced signalling..” Cell Signal 16, no. 8 (August 2004): 929–38. https://doi.org/10.1016/j.cellsig.2004.01.003.
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  - Gonzalez-Gronow, Mario, Michael S. Hershfield, Francisco X. Arredondo-Vega, and Salvatore V. Pizzo. “Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells..” J Biol Chem 279, no. 20 (May 14, 2004): 20993–98. https://doi.org/10.1074/jbc.M401023200.
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  - Gonzalez-Gronow, Mario, Theodosia Kalfa, Carrie E. Johnson, Govind Gawdi, and Salvatore V. Pizzo. “The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells..” J Biol Chem 278, no. 29 (July 18, 2003): 27312–18. https://doi.org/10.1074/jbc.M303172200.
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  - Cuchacovich, Miguel, Héctor Gatica, Paula Vial, Jorge Yovanovich, Salvatore V. Pizzo, and Mario Gonzalez-Gronow. “Streptokinase promotes development of dipeptidyl peptidase IV (CD26) autoantibodies after fibrinolytic therapy in myocardial infarction patients..” Clin Diagn Lab Immunol 9, no. 6 (November 2002): 1253–59. https://doi.org/10.1128/cdli.9.6.1253-1259.2002.
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  - Misra, Uma K., Mario Gonzalez-Gronow, Govind Gawdi, Justin P. Hart, Carrie E. Johnson, and Salvatore V. Pizzo. “The role of Grp 78 in alpha 2-macroglobulin-induced signal transduction. Evidence from RNA interference that the low density lipoprotein receptor-related protein is associated with, but not necessary for, GRP 78-mediated signal transduction..” J Biol Chem 277, no. 44 (November 1, 2002): 42082–87. https://doi.org/10.1074/jbc.M206174200.
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  - Gonzalez-Gronow, Mario, Govind Gawdi, and Salvatore V. Pizzo. “Tissue factor is the receptor for plasminogen type 1 on 1-LN human prostate cancer cells..” Blood 99, no. 12 (June 15, 2002): 4562–67. https://doi.org/10.1182/blood.v99.12.4562.
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  - Cuchacovich, M., H. Gatica, S. V. Pizzo, and M. Gonzalez-Gronow. “Characterization of human serum dipeptidyl peptidase IV (CD26) and analysis of its autoantibodies in patients with rheumatoid arthritis and other autoimmune diseases..” Clin Exp Rheumatol 19, no. 6 (November 2001): 673–80.
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  - Gonzalez-Gronow, M., H. E. Grenett, M. R. Weber, G. Gawdi, and S. V. Pizzo. “Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells..” Biochem J 355, no. Pt 2 (April 15, 2001): 397–407. https://doi.org/10.1042/0264-6021:3550397.
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  - Asplin, I. R., U. K. Misra, G. Gawdi, M. Gonzalez-Gronow, and S. V. Pizzo. “Selective upregulated expression of the alpha2-macroglobulin signaling receptor in highly metastatic 1-LN prostate carcinoma cells..” Arch Biochem Biophys 383, no. 1 (November 1, 2000): 135–41. https://doi.org/10.1006/abbi.2000.2052.
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  - Misra, U. K., G. Gawdi, M. Gonzalez-Gronow, and S. V. Pizzo. “Coordinate regulation of the alpha(2)-macroglobulin signaling receptor and the low density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor by insulin..” J Biol Chem 274, no. 36 (September 3, 1999): 25785–91. https://doi.org/10.1074/jbc.274.36.25785.
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  - Shearin, T. V., S. V. Pizzo, and M. Gonzalez-Gronow. “Molecular abnormalities of human plasminogen isolated from synovial fluid of rheumatoid arthritis patients..” J Mol Med (Berl) 75, no. 5 (May 1997): 378–85.
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  - Misra, U. K., M. Gonzalez-Gronow, G. Gawdi, and S. V. Pizzo. “Up-regulation of the alpha2-macroglobulin signaling receptor on rheumatoid synovial fibroblasts..” J Biol Chem 272, no. 1 (January 3, 1997): 497–502. https://doi.org/10.1074/jbc.272.1.497.
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  - Gonzalez-Gronow, M., M. Cuchacovich, D. M. Grigg, and S. V. Pizzo. “Analysis of autoantibodies to plasminogen in the serum of patients with rheumatoid arthritis..” J Mol Med (Berl) 74, no. 8 (August 1996): 463–69.
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  - Cuchacovich, M., H. Gatica, D. M. Grigg, S. V. Pizzo, and M. Gonzalez-Gronow. “Potential pathogenicity of deglycosylated IgG cross reactive with streptokinase and fibronectin in the serum of patients with rheumatoid arthritis..” J Rheumatol 23, no. 1 (January 1996): 44–51.
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  - Serrano, R. L., P. Rodriguez, S. V. Pizzo, and M. Gonzalez-Gronow. “ATP-regulated activity of the plasmin-streptokinase complex: a novel mechanism involving phosphorylation of streptokinase..” Biochem J 313 ( Pt 1) (January 1, 1996): 171–77. https://doi.org/10.1042/bj3130171.
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  - Gonzalez-Gronow, M., G. Gawdi, and S. V. Pizzo. “Characterization of the plasminogen receptors of normal and rheumatoid arthritis human synovial fibroblasts..” J Biol Chem 269, no. 6 (February 11, 1994): 4360–66.
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  - Gonzalez-Gronow, M., G. Gawdi, and S. V. Pizzo. “Plasminogen activation stimulates an increase in intracellular calcium in human synovial fibroblasts..” J Biol Chem 268, no. 28 (October 5, 1993): 20791–95.
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  - Gonzalez-Gronow, M., J. J. Enghild, and S. V. Pizzo. “Streptokinase and human fibronectin share a common epitope: implications for regulation of fibrinolysis and rheumatoid arthritis..” Biochim Biophys Acta 1180, no. 3 (January 22, 1993): 283–88. https://doi.org/10.1016/0925-4439(93)90051-2.
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  - Stack, M. S., S. V. Pizzo, and M. Gonzalez-Gronow. “Effect of desialylation on the biological properties of human plasminogen..” Biochem J 284 ( Pt 1) (May 15, 1992): 81–86. https://doi.org/10.1042/bj2840081.
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  - Gonzalez-Gronow, M., S. Stack, and S. V. Pizzo. “Plasmin binding to the plasminogen receptor enhances catalytic efficiency and activates the receptor for subsequent ligand binding..” Arch Biochem Biophys 286, no. 2 (May 1, 1991): 625–28. https://doi.org/10.1016/0003-9861(91)90090-6.
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  - Stack, S., M. Gonzalez-Gronow, and S. V. Pizzo. “The effect of divalent cations on the conformation and function of human plasminogen..” Arch Biochem Biophys 284, no. 1 (January 1991): 58–62. https://doi.org/10.1016/0003-9861(91)90263-i.
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  - Gonzalez-Gronow, M., H. E. Grenett, G. M. Fuller, and S. V. Pizzo. “The role of carbohydrate in the function of human plasminogen: comparison of the protein obtained from molecular cloning and expression in Escherichia coli and COS cells..” Biochim Biophys Acta 1039, no. 3 (July 6, 1990): 269–76. https://doi.org/10.1016/0167-4838(90)90259-i.
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  - Edelberg, J. M., J. J. Enghild, S. V. Pizzo, and M. Gonzalez-Gronow. “Neonatal plasminogen displays altered cell surface binding and activation kinetics. Correlation with increased glycosylation of the protein..” J Clin Invest 86, no. 1 (July 1990): 107–12. https://doi.org/10.1172/JCI114671.
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  - Stack, S., M. Gonzalez-Gronow, and S. V. Pizzo. “Regulation of plasminogen activation by components of the extracellular matrix..” Biochemistry 29, no. 20 (May 22, 1990): 4966–70. https://doi.org/10.1021/bi00472a029.
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  - Edelberg, J. M., M. Gonzalez-Gronow, and S. V. Pizzo. “Lipoprotein(a) inhibition of plasminogen activation by tissue-type plasminogen activator..” Thromb Res 57, no. 1 (January 1, 1990): 155–62.
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  - Edelberg, J. M., M. Gonzalez-Gronow, and S. V. Pizzo. “Lipoprotein a inhibits streptokinase-mediated activation of human plasminogen..” Biochemistry 28, no. 6 (March 21, 1989): 2370–74. https://doi.org/10.1021/bi00432a004.
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  - Gonzalez-Gronow, M., J. M. Edelberg, and S. V. Pizzo. “Further characterization of the cellular plasminogen binding site: evidence that plasminogen 2 and lipoprotein a compete for the same site..” Biochemistry 28, no. 6 (March 21, 1989): 2374–77. https://doi.org/10.1021/bi00432a005.
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  - Gonzalez-Gronow, M., and K. C. Robbins. “In vitro biosynthesis of plasminogen in a cell-free system directed by mRNA fractions isolated from monkey liver..” Biochemistry 23, no. 2 (January 17, 1984): 190–96. https://doi.org/10.1021/bi00297a003.
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  - Gonzalez-Gronow, M., G. E. Siefring, and F. J. Castellino. “Mechanism of activation of human plasminogen by the activator complex, streptokinase-plasmin..” J Biol Chem 253, no. 4 (February 25, 1978): 1090–94.
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  - Gonzalez-Gronow, M., B. N. Violand, and F. J. Castellino. “Purification and some properties of the Glu- and Lys-human plasmin heavy chains..” J Biol Chem 252, no. 7 (April 10, 1977): 2175–77.
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- Conference Papers
  - Al-Hashimi, A., B. Shayegan, F. Majeed, P. F. Lebeau, J. Hoogenes, E. Polena, M. Gonzalez-Gronow, S. Pizzo, and R. C. Austin. “Contribution of Anti-GRP78 autoantibodies to prostate cancer progression through tissue factor procoagulant activity.” In Bju International, 115:85–86. WILEY-BLACKWELL, 2015.
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  - Gonzalez-Gronow, M., S. Kaczowka, S. Payne, F. Wang, G. Gawdi, and S. Pizzo. “Plasminogen structural domains exhibit different functions when associated with cell surface GRP78 or VDAC.” In Febs Journal, 274:144–144. BLACKWELL PUBLISHING, 2007.
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Education, Training, & Certifications

Duke Appointment History

Selected Grants

Selected Publications

Academic Articles

Conference Papers