Mst1

MST1 is the acronym for "Macrophage stimulating 1". The MSP protein encoded by the gene of the same name is a glycoprotein that belongs to a family of plasminogen-related growth factors.

MSP is mainly synthesized by hepatocytes as a biologically inactive single chain precursor form (Pro-MSP) and secreted and circulated as a plasma protein. Pro-MSP itself has no biological activity (Wang et al., 2002). The protein is activated by trypsin-like serum-serine proteases such as HGFA, coagulation factor XIIa, coagulation factor XIa, serum kallikrein and binds to its specific receptor tyrosine kinase RON. This process leads to the initiation of several signalling pathways. These include the Ras / mitogen-activated protein kinase, the phosphatidylinositol 3-kinase, the C-Jun amino-terminal kinase and the β-catenin and nuclear factor-kappaB(NF-κB) (Wang et al., 2002; Kretschmann et al. 2010). Expression MSP transcripts are detectable in the liver and to a lesser extent in the adrenal glands, lung, kidney, placenta and pancreas (Ganesan et al., 2011).

MSP was originally identified as a serum protein that activates resident macrophages. (Wang et al., 2002). However, its biological effect is not limited to macrophages. MSP promotes the proliferation and migration of various epithelial cells and microglia (Kretschmann et al., 2010). MSP increases the ciliary motility of nasal epithelial cells (Sakamoto et al.1997), stimulates the bone-resorbing activity of osteoclasts (Kurihara et al., 1996) and stimulates sperm motility (Ohshiro et al. 1996). Several studies have shown that the MSP / RON signalling pathway plays a role in various pathophysiological conditions such as inflammation, wound healing and carcinogenesis.

Inflammation: During inflammation, MSP exerts both a stimulatory and inhibitory dual function on macrophages. The stimulatory functions include the ability to promote macrophage migration and induce phagocytosis and production of cytokines. MSP inhibits the lipopolysaccharide-induced production of inflammatory mediators such as inducible NO synthase, cyclooxygenase-2 and prostaglandin E2. These suppressive effects are mediated by RON-transduced signals that block the LPS-induced activation of NF-κB pathways (Wang et al. 2002; Kretschmann et al. 2010)

Mutations in the MST-1 gene have been associated with inflammatory bowel disease, primary sclerosing cholangitis, extrahepatic cholangiocarcinoma and Merkel cell carcinoma (Krawczyk et al., 2013).

Human MSP shows a high degree of agreement of its amino acid sequences (45%) with the human hepatocyte growth factor (HGF), hence the name "hepatocyte growth factor-like protein (HGFL)".

1. Ganesan R et al (2011) Proteolytic activation of pro-macrophage-stimulating protein by hepsin. Mol Cancer Res 9:1175-1186.
2. Krawczyk M et al (2013) Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma. Dig Liver Dis 45:612-615.
3. Kretschmann KL et al (2010) The macrophage stimulating protein/Ron pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression. Curr drug targets 11:1157-1168.
4. Kurihara N et al (1996) Macrophage-stimulating protein activates STK receptor tyrosine kinase on osteoclasts and facilitates bone resorption by osteoclast-like cells. Blood 87:3704-3710.
5. Nagahama J et al (2011) Tyrosine kinase receptor RON and its ligand MSP in Merkel cell carcinoma. Pathol Res Pract 207:463-467.
6. Ohshiro K et al (1996) Molecular cloning of rat macrophage-stimulating protein and its involvement in the male reproductive system. Biochem Biophys Res Commun 227:273-280.
7. Orikawa H et al (2012) Activation of macrophage-stimulating protein by human airway trypsin-like protease. FEBS Lett 586:217-221.
8. Wang MH et al (2002) Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities. Scand J Immunol 56:545-553.