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Mark R. Frey, PhD

Title(s)Associate Professor Associate Professor of Pediatrics and Biochemistry and Molecular Medicine Admissions Chairs, PIBBS
AddressCHL MailStop137
Off Campus
Los Angeles CA 90089
Phone+1 323 361 5924
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    Title(s)Associate Director of Research

    Title(s)Director of the PhD Program in Biomedical and Biological Sciences


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    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.

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    The role of SPRY2 in the colonic epithelial response to inflammation
    NIH R01DK119694Aug 20, 2019 - May 31, 2023
    Role: Principal Investigator
    The role of the ErbB4 and ErbB3 neuregulin receptors in intestinal epithelial regeneration
    NIH R01DK095004Jul 1, 2013 - May 31, 2023
    Role: Principal Investigator
    Regulation of cyclooxygenase-2 by ErbB4 in colon epithelial cells
    NIH R03DK090295Apr 1, 2011 - Mar 31, 2013
    Role: Principal Investigator
    The role of ErbB-4 in inflammation-induced colon carcinogenesis
    NIH K01DK077956Apr 1, 2007 - Jul 31, 2010
    Role: Principal Investigator

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help. to make corrections and additions.
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    Altmetrics Details PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3ß-mediated restriction of epithelial IL-33. Nat Commun. 2021 02 05; 12(1):836. Schumacher MA, Hsieh JJ, Liu CY, Appel KL, Waddell A, Almohazey D, Katada K, Bernard JK, Bucar EB, Gadeock S, Maselli KM, Washington MK, Grikscheit TC, Warburton D, Rosen MJ, Frey MR. PMID: 33547321.
      View in: PubMed   Mentions:    Fields:    Translation:HumansAnimalsCells
    2. A Little Disorder Can Be Healthy: PRAP1 as a Protective Factor in the Intestine. Cell Mol Gastroenterol Hepatol. 2020; 10(4):855-856. Frey MR. PMID: 32871157.
      View in: PubMed   Mentions:    Fields:    
    3. Behavior-dependent directional tuning in the human visual-navigation network. Nat Commun. 2020 06 26; 11(1):3247. Nau M, Navarro Schröder T, Frey M, Doeller CF. PMID: 32591544.
      View in: PubMed   Mentions:
    4. Intracellular Control of ß-Catenin and Intestinal Cell Fate by SIRT2. Cell Mol Gastroenterol Hepatol. 2020; 10(1):193-194. Frey MR. PMID: 32151608.
      View in: PubMed   Mentions:    Fields:    
    5. A direct comparison of mouse and human intestinal development using epithelial gene expression patterns. Pediatr Res. 2020 07; 88(1):66-76. Stanford AH, Gong H, Noonan M, Lewis AN, Gong Q, Lanik WE, Hsieh JJ, Lueschow SR, Frey MR, Good M, McElroy SJ. PMID: 31242501.
      View in: PubMed   Mentions: 4     Fields:    
    6. Trefoil factor 2 activation of CXCR4 requires calcium mobilization to drive epithelial repair in gastric organoids. J Physiol. 2019 05; 597(10):2673-2690. Engevik KA, Hanyu H, Matthis AL, Zhang T, Frey MR, Oshima Y, Aihara E, Montrose MH. PMID: 30912855.
      View in: PubMed   Mentions: 5     Fields:    Translation:HumansAnimals
    7. Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse. J Pathol. 2019 02; 247(2):254-265. Danopoulos S, Thornton ME, Grubbs BH, Frey MR, Warburton D, Bellusci S, Al Alam D. PMID: 30357827.
      View in: PubMed   Mentions: 7     Fields:    Translation:HumansAnimalsCells
    8. Cellular Plasticity of Defa4Cre-Expressing Paneth Cells in Response to Notch Activation and Intestinal Injury. Cell Mol Gastroenterol Hepatol. 2019; 7(3):533-554. Jones JC, Brindley CD, Elder NH, Myers MG, Rajala MW, Dekaney CM, McNamee EN, Frey MR, Shroyer NF, Dempsey PJ. PMID: 30827941.
      View in: PubMed   Mentions: 9     Fields:    Translation:AnimalsCells
    9. 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. Hou X, Chang DF, Trecartin A, Barthel ER, Schlieve CR, Frey MR, Fowler KL, Grikscheit TC. PMID: 30232817.
      View in: PubMed   Mentions: 1     Fields:    Translation:HumansAnimalsCells
    10. Colon Cancers Get a Negative (Selection) Attitude. Cell Mol Gastroenterol Hepatol. 2018; 6(3):349. Frey MR. PMID: 30182045.
      View in: PubMed   Mentions:    Fields:    Translation:Humans
    11. 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. Golden JM, Escobar OH, Nguyen MVL, Mallicote MU, Kavarian P, Frey MR, Gayer CP. PMID: 29672156.
      View in: PubMed   Mentions: 2     Fields:    Translation:AnimalsCells
    12. Celiac Disease. Gastroenterology. 2018 06; 154(8):2005-2008. Murray JA, Frey MR, Oliva-Hemker M. PMID: 29550590.
      View in: PubMed   Mentions: 1     Fields:    Translation:Humans
    13. SERCA directs cell migration and branching across species and germ layers. Biol Open. 2017 Oct 15; 6(10):1458-1471. Bower DV, Lansdale N, Navarro S, Truong TV, Bower DJ, Featherstone NC, Connell MG, Al Alam D, Frey MR, Trinh LA, Fernandez GE, Warburton D, Fraser SE, Bennett D, Jesudason EC. PMID: 28821490.
      View in: PubMed   Mentions:
    14. Bacterial Encroachment in Metabolic Syndrome: Too Much Togetherness? Cell Mol Gastroenterol Hepatol. 2017 Sep; 4(2):324-325. Frey MR. PMID: 28840187.
      View in: PubMed   Mentions:    Fields:    
    15. The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ. 2017 05; 24(5):855-865. Almohazey D, Lo YH, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, Schumacher MA, Hamilton KE, Lau KS, Shroyer NF, Frey MR. PMID: 28304405.
      View in: PubMed   Mentions: 5     Fields:    Translation:HumansAnimalsCells
    16. ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis. 2017 02 23; 8(2):e2622. Schumacher MA, Hedl M, Abraham C, Bernard JK, Lozano PR, Hsieh JJ, Almohazey D, Bucar EB, Punit S, Dempsey PJ, Frey MR. PMID: 28230865.
      View in: PubMed   Mentions: 12     Fields:    Translation:HumansAnimalsCells
    17. 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. Wieck MM, Schlieve CR, Thornton ME, Fowler KL, Isani M, Grant CN, Hilton AE, Hou X, Grubbs BH, Frey MR, Grikscheit TC. PMID: 28462379.
      View in: PubMed   Mentions: 3     Fields:    
    18. Disease-Associated Microbial Communities in Healthy Relatives: A Bacteria-Filled Crystal Ball? Cell Mol Gastroenterol Hepatol. 2016 Nov; 2(6):710-711. Frey MR. PMID: 28174743.
      View in: PubMed   Mentions:    Fields:    
    19. Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci. 2017 01 01; 130(1):90-96. Miguel JC, Maxwell AA, Hsieh JJ, Harnisch LC, Al Alam D, Polk DB, Lien CL, Watson AJ, Frey MR. PMID: 27026527.
      View in: PubMed   Mentions: 6     Fields:    Translation:AnimalsCells
    20. Regenerating Reputations: Are Wnt and Myc the Good Guys After All? Dig Dis Sci. 2016 Feb; 61(2):327-9. Frey MR. PMID: 26520110.
      View in: PubMed   Mentions:    Fields:    Translation:Animals
    21. Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development. PLoS One. 2016; 11(1):e0146542. Fung CM, White JR, Brown AS, Gong H, Weitkamp JH, Frey MR, McElroy SJ. PMID: 26745886.
      View in: PubMed   Mentions: 10     Fields:    Translation:HumansAnimalsCells
    22. 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. Dossa AY, Escobar O, Golden J, Frey MR, Ford HR, Gayer CP. PMID: 26608185.
      View in: PubMed   Mentions: 17     Fields:    Translation:AnimalsCells
    23. Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J. 2015 Nov; 46(5):1417-29. Buckley S, Shi W, Xu W, Frey MR, Moats R, Pardo A, Selman M, Warburton D. PMID: 26160872.
      View in: PubMed   Mentions: 5     Fields:    Translation:HumansAnimalsCells
    24. 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. Schall KA, Holoyda KA, Grant CN, Levin DE, Torres ER, Maxwell A, Pollack HA, Moats RA, Frey MR, Darehzereshki A, Al Alam D, Lien C, Grikscheit TC. PMID: 26089336.
      View in: PubMed   Mentions: 8     Fields:    Translation:HumansAnimalsCells
    25. ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis. 2015 Jul; 36(7):710-8. Williams CS, Bernard JK, Demory Beckler M, Almohazey D, Washington MK, Smith JJ, Frey MR. PMID: 25916654.
      View in: PubMed   Mentions: 22     Fields:    Translation:HumansAnimalsCells
    26. 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. Al Alam D, Danopoulos S, Schall K, Sala FG, Almohazey D, Fernandez GE, Georgia S, Frey MR, Ford HR, Grikscheit T, Bellusci S. PMID: 25721301.
      View in: PubMed   Mentions: 7     Fields:    Translation:HumansAnimalsCells
    27. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol Ecol. 2015 Feb; 91(2):1-9. Michail S, Lin M, Frey MR, Fanter R, Paliy O, Hilbush B, Reo NV. PMID: 25764541.
      View in: PubMed   Mentions: 49     Fields:    Translation:HumansCells
    28. The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol. 2014 Oct; 184(10):2768-78. McElroy SJ, Castle SL, Bernard JK, Almohazey D, Hunter CJ, Bell BA, Al Alam D, Wang L, Ford HR, Frey MR. PMID: 25216938.
      View in: PubMed   Mentions: 22     Fields:    Translation:HumansAnimalsCells
    29. Tumor necrosis factor induces developmental stage-dependent structural changes in the immature small intestine. Mediators Inflamm. 2014; 2014:852378. Brown KS, Gong H, Frey MR, Pope B, Golden M, Martin K, Obey M, McElroy SJ. PMID: 25242872.
      View in: PubMed   Mentions: 7     Fields:    Translation:HumansAnimals
    30. ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatr Res. 2014 Jan; 75(1-2):127-32. Frey MR, Brent Polk D. PMID: 24402051.
      View in: PubMed   Mentions: 6     Fields:    Translation:HumansAnimalsCells
    31. 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. Williams JM, Duckworth CA, Watson AJ, Frey MR, Miguel JC, Burkitt MD, Sutton R, Hughes KR, Hall LJ, Caamaño JH, Campbell BJ, Pritchard DM. PMID: 24046352.
      View in: PubMed   Mentions: 40     Fields:    Translation:AnimalsCells
    32. 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. Bernard JK, McCann SP, Bhardwaj V, Washington MK, Frey MR. PMID: 23033483.
      View in: PubMed   Mentions: 18     Fields:    Translation:HumansAnimalsCells
    33. FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev Biol. 2012 Sep 15; 369(2):340-8. Al Alam D, Sala FG, Baptista S, Galzote R, Danopoulos S, Tiozzo C, Gage P, Grikscheit T, Warburton D, Frey MR, Bellusci S. PMID: 22819677.
      View in: PubMed   Mentions: 9     Fields:    Translation:AnimalsCells
    34. 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. Hilliard VC, Frey MR, Dempsey PJ, Peek RM, Polk DB. PMID: 21617117.
      View in: PubMed   Mentions: 13     Fields:    Translation:AnimalsCells
    35. 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. Yamaoka T, Frey MR, Dise RS, Bernard JK, Polk DB. PMID: 21617115.
      View in: PubMed   Mentions: 13     Fields:    Translation:AnimalsCells
    36. 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. Hobbs SS, Goettel JA, Liang D, Yan F, Edelblum KL, Frey MR, Mullane MT, Polk DB. PMID: 21566012.
      View in: PubMed   Mentions: 17     Fields:    Translation:AnimalsCells
    37. 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. Rosen MJ, Frey MR, Washington MK, Chaturvedi R, Kuhnhein LA, Matta P, Revetta FL, Wilson KT, Polk DB. PMID: 21308881.
      View in: PubMed   Mentions: 43     Fields:    Translation:HumansCells
    38. Sprouty keeps bowel kinases regular in colon cancer, while miR-21 targets Sprouty. . 2011 Jan 01; 11(1):122-4. Frey MR, Carraro G, Batra RK, Polk DB, Warburton D. PMID: 21124074.
      View in: PubMed   Mentions:
    39. ErbB4 promotes cyclooxygenase-2 expression and cell survival in colon epithelial cells. Lab Invest. 2010 Oct; 90(10):1415-24. Frey MR, Hilliard VC, Mullane MT, Polk DB. PMID: 20585313.
      View in: PubMed   Mentions: 14     Fields:    Translation:HumansAnimalsCells
    40. Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis. 2009 Mar 01; 199(5):641-51. Nagy TA, Frey MR, Yan F, Israel DA, Polk DB, Peek RM. PMID: 19199544.
      View in: PubMed   Mentions: 53     Fields:    Translation:HumansCells
    41. The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF. Gastroenterology. 2009 Jan; 136(1):217-26. Frey MR, Edelblum KL, Mullane MT, Liang D, Polk DB. PMID: 18973758.
      View in: PubMed   Mentions: 41     Fields:    Translation:HumansAnimalsCells
    42. 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. McElroy SJ, Frey MR, Yan F, Edelblum KL, Goettel JA, John S, Polk DB. PMID: 18467504.
      View in: PubMed   Mentions: 16     Fields:    Translation:AnimalsCells
    43. 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. Dise RS, Frey MR, Whitehead RH, Polk DB. PMID: 17991704.
      View in: PubMed   Mentions: 50     Fields:    Translation:AnimalsCells
    44. 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. Chen X, Abair TD, Ibanez MR, Su Y, Frey MR, Dise RS, Polk DB, Singh AB, Harris RC, Zent R, Pozzi A. PMID: 17339338.
      View in: PubMed   Mentions: 50     Fields:    Translation:HumansAnimalsCells
    45. p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration. EMBO J. 2006 Dec 13; 25(24):5683-92. Frey MR, Dise RS, Edelblum KL, Polk DB. PMID: 17139251.
      View in: PubMed   Mentions: 51     Fields:    Translation:HumansAnimalsCells
    46. Cysteine-rich domains of muc3 intestinal mucin promote cell migration, inhibit apoptosis, and accelerate wound healing. Gastroenterology. 2006 Nov; 131(5):1501-17. Ho SB, Dvorak LA, Moor RE, Jacobson AC, Frey MR, Corredor J, Polk DB, Shekels LL. PMID: 17101324.
      View in: PubMed   Mentions: 37     Fields:    Translation:HumansAnimalsCells
    47. 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. Frey MR, Golovin A, Polk DB. PMID: 15316018.
      View in: PubMed   Mentions: 47     Fields:    Translation:AnimalsCells
    48. 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. Frey MR, Clark JA, Bateman NW, Kazanietz MG, Black AR, Black JD. PMID: 15130764.
      View in: PubMed   Mentions: 3     Fields:    Translation:AnimalsCells
    49. 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. Clark JA, Black AR, Leontieva OV, Frey MR, Pysz MA, Kunneva L, Woloszynska-Read A, Roy D, Black JD. PMID: 14670956.
      View in: PubMed   Mentions: 23     Fields:    Translation:AnimalsCells
    50. 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. Frey MR, Leontieva O, Watters DJ, Black JD. PMID: 11301042.
      View in: PubMed   Mentions: 6     Fields:    Translation:AnimalsCells
    51. 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. Frey MR, Clark JA, Leontieva O, Uronis JM, Black AR, Black JD. PMID: 11076962.
      View in: PubMed   Mentions: 29     Fields:    Translation:AnimalsCells
    52. Colonocyte differentiation is associated with increased expression and altered distribution of protein kinase C isozymes. Gastroenterology. 1998 Jul; 115(1):75-85. Verstovsek G, Byrd A, Frey MR, Petrelli NJ, Black JD. PMID: 9649461.
      View in: PubMed   Mentions: 15     Fields:    Translation:Animals
    53. 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. Frey MR, Saxon ML, Zhao X, Rollins A, Evans SS, Black JD. PMID: 9083081.
      View in: PubMed   Mentions: 35     Fields:    Translation:AnimalsCells
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