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 Alvis Faubion, Mary E. Keir, Judy Young, Amitabha Chaudhuri, Robert A. Lazarus, Jackson G. Egen

Research output: Contribution to journalArticle

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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

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inflammatory bowel disease
Inflammatory Bowel Diseases
macrophages
Alleles
alleles
Polymorphism
proteins
genetic polymorphism
Tissue
RON protein
macrophage stimulating protein
Serum
receptors
Crohn disease
Disease Susceptibility
Linkage Disequilibrium
colitis
Receptor Protein-Tyrosine Kinases
Genetic Predisposition to Disease
linkage disequilibrium

ASJC Scopus subject areas

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

Cite this

Kauder, S. E., Santell, L., Mai, E., Wright, L. Y., Luis, E., N'Diaye, E. N., ... 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

Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele. / Kauder, Steven E.; Santell, Lydia; Mai, Elaine; Wright, Lilyan Y.; Luis, Elizabeth; N'Diaye, Elsa N.; Lutman, Jeff; Ratti, Navneet; Sa, Susan M.; Maun, Henry R.; Stefanich, Eric; Gonzalez, Lino C.; Graham, Robert R.; Diehl, Lauri; Faubion, William Alvis; Keir, Mary E.; Young, Judy; Chaudhuri, Amitabha; Lazarus, Robert A.; Egen, Jackson G.

In: PLoS One, Vol. 8, No. 12, e83958, 23.12.2013.

Research output: Contribution to journalArticle

Kauder, SE, Santell, L, Mai, E, Wright, LY, Luis, E, N'Diaye, EN, Lutman, J, Ratti, N, Sa, SM, Maun, HR, Stefanich, E, Gonzalez, LC, Graham, RR, Diehl, L, Faubion, WA, Keir, ME, Young, J, Chaudhuri, A, Lazarus, RA & Egen, JG 2013, 'Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele', PLoS One, vol. 8, no. 12, e83958. https://doi.org/10.1371/journal.pone.0083958
Kauder, Steven E. ; Santell, Lydia ; Mai, Elaine ; Wright, Lilyan Y. ; Luis, Elizabeth ; N'Diaye, Elsa N. ; Lutman, Jeff ; Ratti, Navneet ; Sa, Susan M. ; Maun, Henry R. ; Stefanich, Eric ; Gonzalez, Lino C. ; Graham, Robert R. ; Diehl, Lauri ; Faubion, William Alvis ; Keir, Mary E. ; Young, Judy ; Chaudhuri, Amitabha ; Lazarus, Robert A. ; Egen, Jackson G. / Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele. In: PLoS One. 2013 ; Vol. 8, No. 12.
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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.",
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T1 - Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele

AU - Kauder, Steven E.

AU - Santell, Lydia

AU - Mai, Elaine

AU - Wright, Lilyan Y.

AU - Luis, Elizabeth

AU - N'Diaye, Elsa N.

AU - Lutman, Jeff

AU - Ratti, Navneet

AU - Sa, Susan M.

AU - Maun, Henry R.

AU - Stefanich, Eric

AU - Gonzalez, Lino C.

AU - Graham, Robert R.

AU - Diehl, Lauri

AU - Faubion, William Alvis

AU - Keir, Mary E.

AU - Young, Judy

AU - Chaudhuri, Amitabha

AU - Lazarus, Robert A.

AU - Egen, Jackson G.

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N2 - 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.

AB - 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.

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