title: Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele.
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.
authors.affiliation: Discovery Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kauder
authors.affiliation: Early Discovery Biochemistry, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Lydia
authors.initials: L
authors.lastname: Santell
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.affiliation: Immunology, Tissue Growth and Repair- Diagnostics Discovery, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Lilyan Y
authors.initials: LY
authors.lastname: Wright
authors.affiliation: Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.affiliation: Discovery Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Elsa N
authors.initials: EN
authors.lastname: N'Diaye
authors.affiliation: Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: Lutman
authors.affiliation: Pathology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Navneet
authors.initials: N
authors.lastname: Ratti
authors.affiliation: Pathology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sa
authors.affiliation: Early Discovery Biochemistry, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Maun
authors.affiliation: Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Stefanich
authors.affiliation: Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Lino C
authors.initials: LC
authors.lastname: Gonzalez
authors.affiliation: Immunology, Tissue Growth and Repair -Human Genetics, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.affiliation: Pathology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
authors.affiliation: Immunology, Tissue Growth and Repair- Diagnostics Discovery, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Keir
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Judy
authors.initials: J
authors.lastname: Young
authors.affiliation: Molecular Oncology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Chaudhuri
authors.affiliation: Early Discovery Biochemistry, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lazarus
authors.affiliation: Discovery Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Jackson G
authors.initials: JG
authors.lastname: Egen
mesh_terms: D016475:3T3 Cells; D000483:Alleles; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases