Signaling by MST1 (Homo sapiens)
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Description
Inflammatory mediators such as growth factors produced by macrophages play an important role in the inflammatory response occurring during bacterial infection, tissue injury and immune responses. Many growth factors and their receptor-type protein tyrosine kinases (RTKs) play a critical role in inflammation, wound healing and tissue remodelling. The growth factor hepatocyte growth factor-like protein (MST1, also known as macrophage-stimulating protein, MSP) binds to a specific receptor, macrophage-stimulating protein receptor (MST1R, also known as RON, recepteur d'origine nantais). MST1 belongs to the kringle protein family, which includes HGF and plasminogen. It is produced by the liver and circulates in the blood as a biologically-inactive single chain precursor (pro-MST1). Proteolytic cleavage of pro-MST1 into the biologically-active MST1 dimer is necessary for receptor binding. Cleavage occurs during blood coagulation and at inflammatory sites, the resultant MST1 dimer then binds MST1R receptors on local macrophages. MST1R is ubiquitously expressed but mainly in epithelial cells.
MST1 binding to MST1R promotes receptor homodimerisation which in turn allows autophosphorylation of two tyrosine residues within the catalytic site which regulates kinase activity and allows phosphorylation of the carboxy-terminal binding site of the receptor. The docking site is essential for downstream signaling through direct and indirect binding of SH2 domain-containing adaptor proteins such as GRB2, PI3K, and SRC. MST1/MST1R signaling plays a dual role in regulating inflammation; initially stimulating chemotaxis and phagocytosis (macrophage activation) and then exerts broad inhibitory effects on macrophages, limiting the extent of inflammtory responses (Wang et al. 2002). MST1R is upregulated in many epithelial cancers where it is thought to play a role in the progression of these types of cancer (Kretschmann et al. 2010). View original pathway at Reactome.
MST1 binding to MST1R promotes receptor homodimerisation which in turn allows autophosphorylation of two tyrosine residues within the catalytic site which regulates kinase activity and allows phosphorylation of the carboxy-terminal binding site of the receptor. The docking site is essential for downstream signaling through direct and indirect binding of SH2 domain-containing adaptor proteins such as GRB2, PI3K, and SRC. MST1/MST1R signaling plays a dual role in regulating inflammation; initially stimulating chemotaxis and phagocytosis (macrophage activation) and then exerts broad inhibitory effects on macrophages, limiting the extent of inflammtory responses (Wang et al. 2002). MST1R is upregulated in many epithelial cancers where it is thought to play a role in the progression of these types of cancer (Kretschmann et al. 2010). View original pathway at Reactome.
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The non-synonymous coding variant in MST1 (R689C) has been associated with genetic susceptibility to both Crohn's disease and ulcerative colitis, two major types of inflammatory bowel disease (IBD). The R689C variant reduces the amount of circulating MST1 thereby reducing MST1R activity and down-regulation of the MST1/MST1R signaling pathway (McGovern et al. 2010, Gorlatova et al. 2011, Kauder et al. 2013).