Peter C. Gray
Clayton Foundation Laboratories for Peptide Biology
My research currently focuses on studying Cripto, a GPI-anchored/secreted oncoprotein that controls normal stem cell function and tissue homeostasis by regulating several developmental signaling pathways including TGF-beta and Src/MAPK/PI3K. Cripto is highly expressed in human tumors and promotes tumor cell proliferation, migration, invasion, angiogenesis and EMT. We made the unexpected discovery that Cripto forms a cell surface complex with Glucose Regulated Protein 78 kDa (GRP78), an HSP70 family member that coordinates the unfolded protein response in the ER. GRP78 is best known for its roles as an ER chaperone but it also localizes to the plasma membrane, especially in stem cells and tumor cells. We demonstrated that Cripto binding to cell surface GRP78 is required for Cripto signaling via both TGF-beta and Src/MAPK/PI3K pathways. More recently we discovered that Cripto/GRP78 signaling maintains fetal and adult mammary stem cells suggesting that this pathway similarly regulates other stem cell types and that it may promote an aggressive, undifferentiated phenotype in breast and other human cancers. 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 tumor growth and metastasis in mice. 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.
Disrupting the cell surface Cripto/GRP78 complex blocks Cripto signaling. A) Cripto promotes stemness and tumorigenesis by binding cell surface GRP78 and signaling via Activin/Nodal/TGF-beta and Src/Erk/Akt pathways. B) Disrupting the cell surface Cripto/GRP78 complex blocks Cripto signaling and therefore promotes differentiation and tumor suppression. SubA, GRP78-specific protease; anti-GRP78, neutralizing Ab that blocks Cripto/GRP78 binding; ALK4-Fc, binds soluble Cripto and blocks soluble Cripto signaling via GRP78.
- 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
- Differential requirement of GRP94 and GRP78 in mammary gland development. Zhu G, Wang M, Spike B, Gray PC, Shen J, Lee SH, Chen SY, Lee AS. Sci Rep. 2014 Jun 23;4:5390.
- CRIPTO/GRP78 Signaling Maintains Fetal and Adult Mammary Stem Cells Ex Vivo. Spike BT, Kelber JA, Booker E, Kalathur M, Rodewald R, Lipianskaya J, La J, He M, Wright T, Klemke R, Wahl GM, Gray PC. Stem Cell Reports. 2014 Apr 3;2(4):427-39.
- An Activin A/BMP2 Chimera Displays Bone Healing Properties Superior to Those of BMP2. Yoon BH, Esquivies L, Ahn C, Gray PC, Ye SK, Kwiatkowski W, Choe S. J Bone Miner Res. 2014 Apr 1.
- Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function. Islam MS, Catherino WH, Protic O, Janjusevic M, Gray PC, Giannubilo SR, Ciavattini A, Lamanna P, Tranquilli AL, Petraglia F, Castellucci M, Ciarmela P. J Clin Endocrinol Metab. 2014 May;99(5):E775-85.
- Designer nodal/BMP2 chimeras mimic nodal signaling, promote chondrogenesis, and reveal a BMP2-like structure. Esquivies L, Blackler A, Peran M, Rodriguez-Esteban C, Izpisua Belmonte JC, Booker E, Gray PC, Ahn C, Kwiatkowski W, Choe S. J Biol Chem. 2014 Jan 17;289(3):1788-97.
- RKIP and cytotrophoblast motility. Ciarmela P, Marzioni D, Islam MS, Gray PC, Terracciano L, Lorenzi T, Todros T, Petraglia F, Castellucci M. J Cell Physiol. 2012 Dec;227(12):3895.
- Cripto/GRP78 modulation of the TGF-beta pathway in development and oncogenesis. Gray PC, Vale W. FEBS Lett. 2012 Jul 4;586(14):1836-45.
- Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Ciarmela P, Islam MS, Reis FM, Gray PC, Bloise E, Petraglia F, Vale W, Castellucci M. Hum Reprod Update. 2011 Nov-Dec;17(6):772-90.
- Possible role of RKIP in cytotrophoblast migration: immunohistochemical and in vitro studies. Ciarmela P, Marzioni D, Islam MS, Gray PC, Terracciano L, Lorenzi T, Todros T, Petraglia F, Castellucci M. J Cell Physiol. 2012 May;227(5):1821-8.
- Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid. Ciarmela P, Bloise E, Gray PC, Carrarelli P, Islam MS, De Pascalis F, Severi FM, Vale W, Castellucci M, Petraglia F. J Clin Endocrinol Metab. 2011 Mar;96(3):755-65.
- Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Kelber JA, Panopoulos AD, Shani G, Booker EC, Belmonte JC, Vale WW, Gray PC. Oncogene. 2009 Jun 18;28(24):2324-36.
- Cripto is a noncompetitive activin antagonist that forms analogous signaling complexes with activin and nodal. Kelber JA, Shani G, Booker EC, Vale WW, Gray PC. J Biol Chem. 2008 Feb 22;283(8):4490-500. Epub 2007 Dec 18.
- GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta signaling and enhance cell growth. Shani G, Fischer WH, Justice NJ, Kelber JA, Vale W, Gray PC. Mol Cell Biol. 2008 Jan;28(2):666-77.
- Cripto binds transforming growth factor beta (TGF-beta) and inhibits TGF-beta signaling. Gray PC, Shani G, Aung K, Kelber J, Vale W. Mol Cell Biol. 2006 Dec;26(24):9268-78. Epub 2006 Oct 9. Erratum in: Mol Cell Biol. 2008 Dec;28(23):7260.
- Identification of distinct inhibin and transforming growth factor beta-binding sites on betaglycan:functional separation of betaglycan co-receptor actions. Wiater E, Harrison CA, Lewis KA, Gray PC, Vale WW. J Biol Chem. 2006 Jun 23;281(25):17011-22.
- Antagonists of activin signaling: mechanisms and potential biological applications. Harrison CA, Gray PC, Vale WW, Robertson DM. Trends Endocrinol Metab. 2005 Mar;16(2):73-8.
- Activins and inhibins and their signaling. Vale W, Wiater E, Gray P, Harrison C, Bilezikjian L, Choe S. Ann N Y Acad Sci. 2004 Dec;1038:142-7.
- Modulation of activin and BMP signaling. Harrison CA, Wiater E, Gray PC, Greenwald J, Choe S, Vale W. Mol Cell Endocrinol. 2004 Oct 15;225(1-2):19-24.
- An activin mutant with disrupted ALK4 binding blocks signaling via type II receptors. Harrison CA, Gray PC, Fischer WH, Donaldson C, Choe S, Vale W. J Biol Chem. 2004 Jul 2;279(27):28036-44.
- Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Gray PC, Harrison CA, Vale W. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5193-8.
- Identification of a functional binding site for activin on the type I receptor ALK4. Harrison CA, Gray PC, Koerber SC, Fischer W, Vale W. J Biol Chem. 2003 Jun 6;278(23):21129-35.
- The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Greenwald J, Groppe J, Gray PC, Wiater E, Kwiatkowski W, Vale W, Choe S. Mol Cell. 2003 Mar;11(3):605-17.
- Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan. Gray PC, Bilezikjian LM, Vale W. Mol Cell Endocrinol. 2002 Feb 25;188(1-2):254-60.
- Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM, Vale W. Nature. 2000 Mar 23;404(6776):411-4.
- Identification of a binding site on the type II activin receptor for activin and inhibin. Gray PC, Greenwald J, Blount AL, Kunitake KS, Donaldson CJ, Choe S, Vale W. J Biol Chem. 2000 Feb 4;275(5):3206-12.