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

PLoS One. 2013 Dec 23;8(12):e83958. doi: 10.1371/journal.pone.0083958. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Alleles*
  • Animals
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation
  • Genetic Predisposition to Disease*
  • Hepatocyte Growth Factor / blood
  • Hepatocyte Growth Factor / genetics*
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / metabolism*
  • Inflammatory Bowel Diseases / pathology
  • Intestines / pathology
  • Mice
  • Models, Molecular
  • Polymorphism, Genetic*
  • Protein Conformation
  • Proteolysis
  • Proto-Oncogene Proteins / blood
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction

Substances

  • Proto-Oncogene Proteins
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • RON protein
  • Receptor Protein-Tyrosine Kinases

Grant support

This work was supported by Genentech, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.