Macrophage stimulating protein (MSP), also known as HGF-like protein, and scatter factor-2, is a member of the HGF family of growth factors. MSP is secreted as an inactive single chain precursor (pro-MSP) that contains a PAN/APPLE-like domain, four kringle domains, and a peptidase S1 domain which lacks enzymatic activity. Mouse MSP shares 79% and 93% aa sequence identity with human and rat MSP, respectively and 42% aa sequence identity with mouse HGF. Pro-MSP is secreted by hepatocytes under the positive and negative control of CBP in complex with either HNF-4 or RAR, respectively. Circulating pro-MSP is proteolytically cleaved in response to tissue injury to yield biologically active disulfide linked heterodimers consisting of a 45-62kD alpha and a 25-35kD beta chain. Pro-MSP can be activated by MT-SP1, a transmembrane protease that is expressed on macrophages and is upregulated in many cancers. Heterodimeric MSP, as well as the isolated beta chain, binds to MSP R/Ron with high-affinity, although only heterodimeric MSP can induce receptor dimerization and signaling. MSP induces macrophage and keratinocyte proliferation and osteoclast activation. It also inhibits LPS- or IFN-induced iNOS and IL-12 expression by macrophages and prevents apoptosis of epithelial cells separated from the ECM. The substitution of cysteine 672 (in the beta chain) with alanine significantly increases the bioactivity of recombinant human MSP, apparently by limiting incorrect disulfide bond formation between the alpha and beta chains.