Mark R. Frey, PhD

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.

• Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunityImmunity. 2024 Feb 13; 57(2):319-332. e6. . View in PubMed
• Deep Crypt Secretory Cell Differentiation in the Colonic Epithelium Is Regulated by Sprouty2 and Interleukin 13 Cell Mol Gastroenterol Hepatol. 2023; 15(4):971-984. . View in PubMed
• Deletion of Endogenous Neuregulin-4 Limits Adaptive Immunity During Interleukin-10 Receptor-Neutralizing Colitis Inflamm Bowel Dis. 2023 11 02; 29(11):1778-1792. . View in PubMed
• Sonic Hedgehog: Powering up Intestinal Regeneration? Cell Mol Gastroenterol Hepatol. 2023; 16(4):650-651.. View in PubMed
• Correction: Loss of miR-24-3p promotes epithelial cell apoptosis and impairs the recovery from intestinal inflammation Cell Death Dis. 2022 Feb 10; 13(2):135. . View in PubMed
• An American Physiological Society cross-journal Call for Papers on “The Physiology of Obesity” Am J Physiol Lung Cell Mol Physiol. 2022 11 01; 323(5):L593-L602. . View in PubMed
• Scoping out the future: American Journal of Physiology-Gastrointestinal and Liver Physiology Am J Physiol Gastrointest Liver Physiol. 2021 07 01; 321(1):G52-G54. . View in PubMed
• NRG4-ErbB4 signaling represses proinflammatory macrophage activity Am J Physiol Gastrointest Liver Physiol. 2021 06 01; 320(6):G990-G1001. . View in PubMed
• Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3ß-mediated restriction of epithelial IL-33 Nat Commun. 2021 02 05; 12(1):836. . View in PubMed
• Loss of miR-24-3p promotes epithelial cell apoptosis and impairs the recovery from intestinal inflammation Cell Death Dis. 2021 12 18; 13(1):8. . View in PubMed
• Success of Distance Learning During 2020 COVID-19 Restrictions: A Report from Five STEM Training Programs for Underrepresented High School and Undergraduate Learners J STEM Outreach. 2021; 4(3). . View in PubMed
• The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling Front Endocrinol (Lausanne). 2021; 12:799648. . View in PubMed
• An American Physiological Society cross-journal Call for Papers on “Inter-Organ Communication in Homeostasis and Disease” Am J Physiol Lung Cell Mol Physiol. 2021 07 01; 321(1):L42-L49. . View in PubMed
• A direct comparison of mouse and human intestinal development using epithelial gene expression patterns Pediatr Res. 2020 07; 88(1):66-76. . View in PubMed
• A Little Disorder Can Be Healthy: PRAP1 as a Protective Factor in the Intestine Cell Mol Gastroenterol Hepatol. 2020; 10(4):855-856. . View in PubMed
• Intracellular Control of ß-Catenin and Intestinal Cell Fate by SIRT2 Cell Mol Gastroenterol Hepatol. 2020; 10(1):193-194. . View in PubMed
• Behavior-dependent directional tuning in the human visual-navigation network Nat Commun. 2020 06 26; 11(1):3247. . View in PubMed
• Trefoil factor 2 activation of CXCR4 requires calcium mobilization to drive epithelial repair in gastric organoids J Physiol. 2019 05; 597(10):2673-2690. . View in PubMed
• Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse J Pathol. 2019 02; 247(2):254-265. . View in PubMed
• Cellular Plasticity of Defa4Cre-Expressing Paneth Cells in Response to Notch Activation and Intestinal Injury Cell Mol Gastroenterol Hepatol. 2019; 7(3):533-554. . View in PubMed
• Short-term and long-term human or mouse organoid units generate tissue-engineered small intestine without added signalling molecules Exp Physiol. 2018 12; 103(12):1633-1644. . View in PubMed
• Celiac Disease Gastroenterology. 2018 06; 154(8):2005-2008. . View in PubMed
• Colon Cancers Get a Negative (Selection) Attitude Cell Mol Gastroenterol Hepatol. 2018; 6(3):349. . View in PubMed
• Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms Am J Physiol Gastrointest Liver Physiol. 2018 08 01; 315(2):G259-G271. . View in PubMed
• SERCA directs cell migration and branching across species and germ layers Biol Open. 2017 Oct 15; 6(10):1458-1471. . View in PubMed
• Bacterial Encroachment in Metabolic Syndrome: Too Much Togetherness? Cell Mol Gastroenterol Hepatol. 2017 Sep; 4(2):324-325.. View in PubMed
• Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell NicheCell Mol Gastroenterol Hepatol. 2017 May; 3(3):367-388. e1. . View in PubMed
• Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell NicheCell 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 05; 24(5):855-865. . View in PubMed
• Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway J Cell Sci. 2017 01 01; 130(1):90-96. . View in PubMed
• ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation Cell Death Dis. 2017 02 23; 8(2):e2622. . View in PubMed
• 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
• 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
• 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; 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
• 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
• 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
• 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
• 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 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 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
• 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

• Lenz, Heinz-Josef
• Schumacher, Michael
• McMahon, Andrew