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Mark R. Frey, PhD
Assistant Professor of Pediatrics
CHL MailStop137 Off Campus Los Angeles
+1 323 361 5924


My laboratory’s research program is focused on the role of ErbB receptor tyrosine kinases in intestinal homeostasis and health. In particular, we are investigating how the neuregulin receptors ErbB4 and ErbB3 help maintain intestinal epithelial barrier integrity in the face of injury and inflammation. We were the first to report a functional role for ErbB4 in the intestine, showing that it is up-regulated in response to injury and necessary for survival of colon epithelial cells in the presence of TNF. We further demonstrated that the ErbB4-specific ligand NRG4 is protective in rodent models of inflammatory bowel disease and necrotizing enterocolitis.

While ErbB receptor activation is potentially therapeutic for intestinal inflammation, altered expression or activity in the context of colorectal cancer could make this pathway a double-edged sword. We have demonstrated that ErbB4 expression is elevated in a substantial subset of human colon tumors. Furthermore, ErbB4 overexpression can enhance mutant Ras- and Apc-driven colonocyte transformation. Interestingly, however, it is not able to drive transformation on its own, and a subset of human tumors have quite low expression. Thus, while ErbB4 is neither necessary nor sufficient to drive tumorigenesis, it can enhance the survival of transformed cells, and targeting ErbB4 in tumors that over-express it is a potential avenue for inhibiting tumor cell survival.

Research Interests: Signal transduction, wound healing, inflammation

Disease Models: Cell, enteroid, and in vivo models of inflammatory bowel disease, colitis-associated colon cancer, and necrotizing enterocolitis.


Miguel JC, Maxwell AA, Hsieh JJ, Harnisch LC, Al Alam D, Polk DB, Lien CL, Watson AJ, Frey MR. Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci. 2016 Mar 29. View in: PubMed

Frey MR. Regenerating Reputations: Are Wnt and Myc the Good Guys After All? Dig Dis Sci. 2016 Feb; 61(2):327-9. View in: PubMed

Dossa AY, Escobar O, Golden J, Frey MR, Ford HR, Gayer CP. Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling. Am J Physiol Gastrointest Liver Physiol. 2016 Jan 15; 310(2):G81-92. View in: PubMed

Fung CM, White JR, Brown AS, Gong H, Weitkamp JH, Frey MR, McElroy SJ. Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development. PLoS One. 2016; 11(1):e0146542. View in: PubMed

Buckley S, Shi W, Xu W, Frey MR, Moats R, Pardo A, Selman M, Warburton D. Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J. 2015 Nov; 46(5):1417-29. View in: PubMed

Williams CS, Bernard JK, Demory Beckler M, Almohazey D, Washington MK, Smith JJ, Frey MR. ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis. 2015 Jul; 36(7):710-8. View in: PubMed

Al Alam D, Danopoulos S, Schall K, Sala FG, Almohazey D, Fernandez GE, Georgia S, Frey MR, Ford HR, Grikscheit T, Bellusci S. Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2015 Apr 15; 308(8):G678-90. View in: PubMed

Michail S, Lin M, Frey MR, Fanter R, Paliy O, Hilbush B, Reo NV. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol Ecol. 2015 Feb; 91(2):1-9. View in: PubMed

McElroy SJ, Castle SL, Bernard JK, Almohazey D, Hunter CJ, Bell BA, Al Alam D, Wang L, Ford HR, Frey MR. The ErbB4 Ligand Neuregulin-4 Protects against Experimental Necrotizing Enterocolitis. Am J Pathol. 2014 Oct; 184(10):2768-78. View in: PubMed

Brown KS, Gong H, Frey MR, Pope B, Golden M, Martin K, Obey M, McElroy SJ. Tumor necrosis factor induces developmental stage-dependent structural changes in the immature small intestine. Mediators Inflamm. 2014; 2014:852378. View in: PubMed

Frey MR, Brent Polk D. ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatr Res. 2014 Jan; 75(1-2):127-32. View in: PubMed

Williams JM, Duckworth CA, Watson AJ, Frey MR, Miguel JC, Burkitt MD, Sutton R, Hughes KR, Hall LJ, Caamaño JH, Campbell BJ, Pritchard DM. A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Dis Model Mech. 2013 Nov-Dec; 6(6):1388-99. View in: PubMed

Bernard JK, McCann SP, Bhardwaj V, Washington MK, Frey MR. Neuregulin-4 is a survival factor for colon epithelial cells both in culture and in vivo. J Biol Chem. 2012 Nov 16; 287(47):39850-8. View in: PubMed

Al Alam D, Sala FG, Baptista S, Galzote R, Danopoulos S, Tiozzo C, Gage P, Grikscheit T, Warburton D, Frey MR, Bellusci S. FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev Biol. 2012 Sep 15; 369(2):340-8. View in: PubMed

Rosen MJ, Frey MR, Washington MK, Chaturvedi R, Kuhnhein LA, Matta P, Revetta FL, Wilson KT, Polk DB. STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction. Inflamm Bowel Dis. 2011 Nov; 17(11):2224-34. View in: PubMed

Yamaoka T, Frey MR, Dise RS, Bernard JK, Polk DB. Specific epidermal growth factor receptor autophosphorylation sites promote mouse colon epithelial cell chemotaxis and restitution. Am J Physiol Gastrointest Liver Physiol. 2011 Aug; 301(2):G368-76. View in: PubMed

Hobbs SS, Goettel JA, Liang D, Yan F, Edelblum KL, Frey MR, Mullane MT, Polk DB. TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011 Aug; 301(2):G220-9. View in: PubMed

Hilliard VC, Frey MR, Dempsey PJ, Peek RM, Polk DB. TNF-a converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival. Am J Physiol Gastrointest Liver Physiol. 2011 Aug; 301(2):G338-46. View in: PubMed

Frey MR, Carraro G, Batra RK, Polk DB, Warburton D. Sprouty keeps bowel kinases regular in colon cancer, while miR-21 targets Sprouty. Cancer Biol Ther. 2011 Jan 1; 11(1):122-4. View in: PubMed

Frey MR, Hilliard VC, Mullane MT, Polk DB. ErbB4 promotes cyclooxygenase-2 expression and cell survival in colon epithelial cells. Lab Invest. 2010 Oct; 90(10):1415-24. View in: PubMed

Nagy TA, Frey MR, Yan F, Israel DA, Polk DB, Peek RM. Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis. 2009 Mar 1; 199(5):641-51. View in: PubMed

Frey MR, Edelblum KL, Mullane MT, Liang D, Polk DB. The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF. Gastroenterology. 2009 Jan; 136(1):217-26. View in: PubMed

McElroy SJ, Frey MR, Yan F, Edelblum KL, Goettel JA, John S, Polk DB. Tumor necrosis factor inhibits ligand-stimulated EGF receptor activation through a TNF receptor 1-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2008 Aug; 295(2):G285-93. View in: PubMed

Dise RS, Frey MR, Whitehead RH, Polk DB. Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2008 Jan; 294(1):G276-85. View in: PubMed

Chen X, Abair TD, Ibanez MR, Su Y, Frey MR, Dise RS, Polk DB, Singh AB, Harris RC, Zent R, Pozzi A. Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation. Mol Cell Biol. 2007 May; 27(9):3313-26. View in: PubMed

Frey MR, Dise RS, Edelblum KL, Polk DB. p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration. EMBO J. 2006 Dec 13; 25(24):5683-92. View in: PubMed

Ho SB, Dvorak LA, Moor RE, Jacobson AC, Frey MR, Corredor J, Polk DB, Shekels LL. Cysteine-rich domains of muc3 intestinal mucin promote cell migration, inhibit apoptosis, and accelerate wound healing. Gastroenterology. 2006 Nov; 131(5):1501-17. View in: PubMed

Frey MR, Golovin A, Polk DB. Epidermal growth factor-stimulated intestinal epithelial cell migration requires Src family kinase-dependent p38 MAPK signaling. J Biol Chem. 2004 Oct 22; 279(43):44513-21. View in: PubMed

Frey MR, Clark JA, Bateman NW, Kazanietz MG, Black AR, Black JD. Cell cycle- and protein kinase C-specific effects of resiniferatoxin and resiniferonol 9,13,14-ortho-phenylacetate in intestinal epithelial cells. Biochem Pharmacol. 2004 May 15; 67(10):1873-86. View in: PubMed

Clark JA, Black AR, Leontieva OV, Frey MR, Pysz MA, Kunneva L, Woloszynska-Read A, Roy D, Black JD. Involvement of the ERK signaling cascade in protein kinase C-mediated cell cycle arrest in intestinal epithelial cells. J Biol Chem. 2004 Mar 5; 279(10):9233-47. View in: PubMed

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