Total length: 4817 bp; mRNA product length: 2348 bp.

The human MST1 gene structure consists of 18 exons and 17 introns spanning 4817 bp. One transcript of 2348 bps mRNA encode for 711 amino acid.

There are no known pseudogenes.

MSP was originally identified by E.J. Leonard as a serum protein that activates murine resident peritoneal macrophages (Skeel et al., 1991). The specific receptor for MSP is recepteur dorigine nantais (RON) tyrosine kinase, a member of the MET proto-oncogene family (Wang et al., 2002).

The human MSP has the highest amino acid sequence similarity (45%) to human hepatocyte growth factor (HGF), hence its name "hepatocyte growth factor-like protein (HGFL)". MSP is a glycoprotein belonging to a plasminogen-related growth factor family. It is secreted as a single-chain precursor protein (pro-MSP), which has no biological activity (Wang et al., 2002). Pro-MSP becomes active after cleavage at the Arg483-Val484 bond by specific trypsin-like serine proteases such as hepatocyte growth factor activator (HGFA), ST14 (matriptase), hepsin (transmembrane protease, serine 1; TMPRSS1), TMPRSS11D (Human airway trypsin-like protease; HAT), clotting factor XIIa, clotting factor XIa, and serum kallikrein (Wang et al., 2002; Kawaguchi et al., 2009; Bhatt et al., 2007; Ganesan et al., 2011; Orikawa et al., 2012). Among them, HGFA is a physiological serum activator of MSP at site of tissue injury, and ST14/matriptase likely has significant roles in activation of MSP/RON signaling on the cell surface as a cellular activator. In respiratory epithelial cells, TMPRSS11D/HAT serves as an efficient activator of MSP. In addition, hepsin may have a role in cancer cells. After cleavage of pro-MSP, MSP β-chain binds to its specific receptor tyrosine kinase RON, which results in autophosphorylation within its kinase catalytic domain, leading to the initiation of multiple signaling pathways including Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase, c-Jun amino terminal kinase, β-catenin and nuclear factor-kappaB (NF-κB) (Wang et al., 2002; Kretschmann et al., 2010).

MSP transcripts are present in the liver and, to a lesser amount, in adrenal glands, lungs, kidney, placenta and pancreas (Yoshimura et al., 1993; Ganesan et al., 2011).

MSP is synthesized and secreted mainly by hepatocytes as a biologically inactive single-chain precursor form and circulate as a plasma protein. The concentration of pro-MSP in the plasma is about 2-5 nM (Wang et al., 2002). Pro-MSP is activated by trypsin-like serum serine proteases such as HGFA, clotting factor XIIa, clotting factor XIa, serum kallikrein. On the cell surface, this activation can be processed by membrane-anchored serine proteases such as ST14/matriptase, hepsin and TMPRSS11D/HAT.

MSP was originally identified as a serum protein that activates resident macrophages, such as induction of shape change and motility, enhanced chemotaxis in response to complement factor C5a (Wang et al., 2002). However, its biological effects are not restricted to macrophages. MSP promotes proliferation and migration of various epithelial cells and microglia (Kretschmann et al., 2010; Suzuki et al., 2008), increases 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). To date, many studies have suggested that MSP/RON signaling pathway plays roles in various pathophysiological conditions such as inflammation, wound healing, and cancer. Gene knockout studies revealed that MSP is not essential for embryogenesis, fertility (Bezerra et al., 1998).

Inflammation
During inflammation, MSP exerts a dual function, both stimulatory and inhibitory, on macrophages. Stimulatory functions include its ability to induce macrophage spreading, migration, phagocytosis and the production of cytokines. However, MSP inhibits 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 LPS-induced activation of NF-κB pathways (Wang et al., 2002; Kretschmann et al., 2010).

Wound healing
MSP/RON signaling is involved at various steps of wound healing process. MSP promotes keratinocyte migration in mouse wound models and in wound healing assays in vitro. In experimental excisional wounds in rats, expression levels of MSP and RON within the wound were highest between 7 and 21 days. In a lung injury model, the function of MSP/RON appears to be necessary to suppress NF-κB activation and RON deficient mice exhibited increased lung injury and significantly decreased survival times (Kretschmann et al., 2010). However, MSP deficient mice do not show any defects in a skin wound healing model, suggesting that functional redundancies exist in the wound healing process (Bezerra et al., 1998). In a gentamicin(GM)-induced nephropathy model, MSP attenuates GM-induced inflammation and apoptosis by inhibition of the MAPKs/NF-κB signaling pathways (Lee et al., 2013).

The human MSP has 45% amino acid sequence identity to hepatocyte growth factor, 43% to plasminogen and 36% to prothrombin, and 79% identity with murine and rat orthologue.

Non-synonymous SNP (rs3197999, R689C) in the human MST-1 gene has been linked to inflammatory bowel disease (IBD) (Goyette et al., 2008; Latiano et al., 2010). This R689C variant impairs MSP function by reducing its affinity to RON. Recent study suggests that the rs3197999 variant in MST1 gene is also associated with primary sclerosing cholangitis (PSC) and extrahepatic cholangiocarcinoma (Melum et al., 2011; Srivastava et al., 2012; Krawczyk et al., 2013).