Faculty

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

Overview

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.

Publications

Bacterial Encroachment in Metabolic Syndrome: Too Much Togetherness? Cell Mol Gastroenterol Hepatol. Bacterial Encroachment in Metabolic Syndrome: Too Much Togetherness? Cell Mol Gastroenterol Hepatol. 2017 Sep; 4(2):324-325. View in: PubMed

SERCA directs cell migration and branching across species and germ layers. Biol Open. 2017 Aug 17. View in: PubMed

The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ. 2017 May; 24(5):855-865. View in: PubMed

Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche. Cell Mol Gastroenterol Hepatol. 2017 May; 3(3):367-388. e1. View in: PubMed

The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ. 2017 Mar 17. View in: PubMed

ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis. 2017 Feb 23; 8(2):e2622. View in: PubMed

Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci. 2017 Jan 01; 130(1):90-96. View in: PubMed

Disease-Associated Microbial Communities in Healthy Relatives: A Bacteria-Filled Crystal Ball? Cell Mol Gastroenterol Hepatol. Disease-Associated Microbial Communities in Healthy Relatives: A Bacteria-Filled Crystal Ball? Cell Mol Gastroenterol Hepatol. 2016 Nov; 2(6):710-711. View in: PubMed

Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci. 2016 Mar 29. View in: PubMed

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

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

Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development. PLoS One. 2016; 11(1):e0146542. View in: PubMed

Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J. 2015 Nov; 46(5):1417-29. View in: PubMed

Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 01; 309(3):G135-45. View in: PubMed

Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 1; 309(3):G135-45. View in: PubMed

ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis. 2015 Jul; 36(7):710-8. View in: PubMed

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

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

The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol. 2014 Oct; 184(10):2768-78. View in: PubMed

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

Tumor necrosis factor induces developmental stage-dependent structural changes in the immature small intestine. Mediators Inflamm. 2014; 2014:852378. View in: PubMed

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

A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Dis Model Mech. 2013 Nov; 6(6):1388-99. View in: PubMed

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

FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev Biol. 2012 Sep 15; 369(2):340-8. View in: PubMed

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

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

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

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

Sprouty keeps bowel kinases regular in colon cancer, while miR-21 targets Sprouty. Cancer Biol Ther. 2011 Jan 01; 11(1):122-4. View in: PubMed

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

ErbB4 promotes cyclooxygenase-2 expression and cell survival in colon epithelial cells. Lab Invest. 2010 Oct; 90(10):1415-24. View in: PubMed

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

Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis. 2009 Mar 01; 199(5):641-51. View in: PubMed

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

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

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

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

p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration. EMBO J. 2006 Dec 13; 25(24):5683-92. View in: PubMed

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

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

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

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

Involvement of the ERK signaling cascade in protein kinase C-mediated cell cycle arrest in intestinal epithelial cells. J Biol Chem. 2004 Mar 05; 279(10):9233-47. View in: PubMed

Stimulation of protein kinase C-dependent and -independent signaling pathways by bistratene A in intestinal epithelial cells. Biochem Pharmacol. 2001 May 01; 61(9):1093-100. View in: PubMed

Stimulation of protein kinase C-dependent and -independent signaling pathways by bistratene A in intestinal epithelial cells. Biochem Pharmacol. 2001 May 1; 61(9):1093-100. View in: PubMed

Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium. J Cell Biol. 2000 Nov 13; 151(4):763-78. View in: PubMed

Colonocyte differentiation is associated with increased expression and altered distribution of protein kinase C isozymes. Gastroenterology. 1998 Jul; 115(1):75-85. View in: PubMed

Protein kinase C isozyme-mediated cell cycle arrest involves induction of p21(waf1/cip1) and p27(kip1) and hypophosphorylation of the retinoblastoma protein in intestinal epithelial cells. J Biol Chem. 1997 Apr 04; 272(14):9424-35. View in: PubMed

Protein kinase C isozyme-mediated cell cycle arrest involves induction of p21(waf1/cip1) and p27(kip1) and hypophosphorylation of the retinoblastoma protein in intestinal epithelial cells. J Biol Chem. 1997 Apr 4; 272(14):9424-35. View in: PubMed

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