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Peter C. Gray
Staff Scientist
Clayton Foundation Laboratories for Peptide Biology
Currently, our research focuses on Cripto, a GPI-anchored developmental oncoprotein that is highly expressed in human tumors but not their normal tissue counterparts. Cripto promotes several aspects of tumor growth and metastasis and modulates signaling by TGF-beta ligands while also activating ras/MAPK and PI3K/Akt pathways. Although the mechanisms through which Cripto exerts its effects on these signaling pathways have largely remained obscure, we recently showed that Cripto binds activin-A and TGF-beta1 and inhibits the cytostatic effects of these ligands. More recently, we made the unexpected discovery that Cripto forms a cell surface complex with Glucose Regulated Protein 78 kDa (GRP78), an ER chaperone and HSP70 family member. GRP78 is expressed at the plasma membrane of tumor cells and our recent data indicate that the cell surface interaction between Cripto and GRP78 is required for Cripto activity including its oncogenic effects and its ability to signal via TGF-beta and MAPK/PI3K pathways. We are currently attempting to elucidate the molecular mechanisms of Cripto/GRP78 complex formation and signaling and we are also testing if Cripto and GRP78 function cooperatively to promote the tumorigenic phenotype in vivo. In addition, we are developing reagents including antibodies, peptides and small molecules designed to specifically disrupt the Cripto/GRP78 interface. These reagents are predicted to block oncogenic Cripto function and may lead to future therapies for the treatment of human cancers.
Education
- B.S., Western Washington University, Bellingham
- Ph.D., Pharmacology, University of Washington, Seattle
Awards and Honors
- NIH Director's Bridge Award
- American Association for Cancer Research Scholar in Training Award
- Quest Diagnostics Young Investigator Award
- George E. Hewitt Foundation for Medical Research Fellowship
Selected Publications
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Kelber JA, Panopoulos AD, Shani G, Booker EC, Belmonte JC, Vale WW, Gray PC (2009). Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene 2009 Jun 18;28(24):2324-36.
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Kelber JA, Shani G, Booker EC, Vale WW, Gray PC (2008). Cripto is a noncompetitive activin antagonist that forms analogous signaling complexes with activin and nodal. J Biol Chem. 283(8):4490-500.
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Shani, G., Fischer W. H., Justice, N. J., Kelber, J., Vale, W. and Gray PC (2008). GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit TGF-b signaling and enhance cell growth. Mol. Cell Biol. 28(2):666-77.
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Wiater E, Harrison CA, Lewis KA Gray PC, Vale W.W. (2006). Identification of Distinct Inhibin and Transforming Growth Factor beta-binding Sites on Betaglycan: Functional Separation of Betaglycan Co-receptor Actions. J. Biol. Chem. 281(25):17011-22.
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Gray, PC, Shani, G., Aung, K., Kelber, J and Vale W (2006). Cripto binds TGF-b and inhibits TGF-b signaling. Mol. Cell Biol. 26(24):9268-78.
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Harrison CA, Gray PC, Vale WW, Robertson DM (2005). Antagonists of activin signaling: mechanisms and potential biological applications. Trends Endocrinol Metab. 16(2):73-8.
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Harrison, CA, Wiater, E, Gray, PC, Greenwald, J, Choe, S and Vale, W (2004). Modulation of activin and BMP signaling. Mol Cell Endocrinol 225 (1-2): 19-24.
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Harrison, CA*, Gray, PC*, Fischer, WH, Donaldson, C, Choe, S and Vale W (2004). An activin mutant with disrupted ALK4 binding blocks signaling via type II receptors. J Biol Chem. 279 (27); 28036-44. *Equal contribution.
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Gray, PC, Harrison, CA and Vale, W (2003). Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proc Natl Acad Sci USA, 100: 5193-5198.
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Harrison, CA*, Gray, PC*, Koerber, SC, Fischer, W and Vale W (2003). Identification of a functional binding site for activin on the type I receptor ALK4. J Biol Chem. 278 (23): 21129-35. *Equal contribution.
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Greenwald J, Groppe J, Gray PC, Wiater E, Kwiatkowski W, Vale W, Choe S (2003). The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol. Cell, 11: 605-617.
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Gray, PC, Bilezikjian, LM and Vale W (2002). Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan. Mol Cell Endocrinol 188 (1-2): 253-60.
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Lewis, KA, Gray, PC, Blount, AL, MacConell, LA, Wiater, E, Bilezikjian, LM and Vale, W (2000). Betaglycan binds inhibin and can mediate functional antagonism of activin signaling. Nature 404 (6776): 411-4.
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Gray, PC, Greenwald, J, Blount, AL, Kunitake, KS, Donaldson, CJ, Choe, S and Vale, W (2000). Identification of a binding site on the type II activin receptor for activin and inhibin. J Biol Chem 275 (5): 3206-12.