Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele

Steven E. Kauder, Lydia Santell, Elaine Mai, Lilyan Y. Wright, Elizabeth Luis, Elsa N. N'Diaye, Jeff Lutman, Navneet Ratti, Susan M. Sa, Henry R. Maun, Eric Stefanich, Lino C. Gonzalez, Robert R. Graham, Lauri Diehl, William A. Faubion, Mary E. Keir, Judy Young, Amitabha Chaudhuri, Robert A. Lazarus, Jackson G. Egen

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10 Scopus citations

Abstract

Background: Macrophage stimulating protein (MSP) is a serum growth factor that binds to and activates the receptor tyrosine kinase, Recepteur d'Origine Nantais (RON). A non-synonymous coding variant in MSP (689C) has been associated with genetic susceptibility to both Crohn's disease and ulcerative colitis, two major types of inflammatory bowel disease (IBD) characterized by chronic inflammation of the digestive tract. We investigated the consequences of this polymorphism for MSP-RON pathway activity and IBD pathogenesis. Methods: RON expression patterns were examined on mouse and human cells and tissues under normal and disease conditions to identify cell types regulated by MSP-RON. Recombinant MSP variants were tested for their ability to bind and stimulate RON and undergo proteolytic activation. MSP concentrations were quantified in the serum of individuals carrying the MSP 689R and 689C alleles. Results: In intestinal tissue, RON was primarily expressed by epithelial cells under normal and disease conditions. The 689C polymorphism had no impact on the ability of MSP to bind to or signal through RON. In a cohort of normal individuals and IBD patients, carriers of the 689C polymorphism had lower concentrations of MSP in their serum. Conclusions: By reducing the quantities of circulating MSP, the 689C polymorphism, or a variant in linkage disequilibrium with this polymorphism, may impact RON ligand availability and thus receptor activity. Given the known functions of RON in regulating wound healing and our analysis of RON expression patterns in human intestinal tissue, these data suggest that decreased RON activity may impact the efficiency of epithelial repair and thus underlie the increased IBD susceptibility associated with the MSP 689C allele.

Original languageEnglish (US)
Article numbere83958
JournalPloS one
Volume8
Issue number12
DOIs
StatePublished - Dec 23 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Kauder, S. E., Santell, L., Mai, E., Wright, L. Y., Luis, E., N'Diaye, E. N., Lutman, J., Ratti, N., Sa, S. M., Maun, H. R., Stefanich, E., Gonzalez, L. C., Graham, R. R., Diehl, L., Faubion, W. A., Keir, M. E., Young, J., Chaudhuri, A., Lazarus, R. A., & Egen, J. G. (2013). Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele. PloS one, 8(12), [e83958]. https://doi.org/10.1371/journal.pone.0083958