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Hepatocyte growth factor activator is a serum activator of single‐chain precursor macrophage‐stimulating protein

Macrophage‐stimulating protein (MSP) is a plasma protein that circulates as a single‐chain proform. It acquires biological activity after proteolytic cleavage at the Arg483–Val484 bond, a process in which serum and cell surface serine proteinases have been implicated. In this article, we report that hepatocyte growth factor activator (HGFA), a serum proteinase which activates hepatocyte growth factor in response to tissue injury, may have a critical role in the activation of pro‐MSP. In vitro analysis has revealed that human HGFA efficiently cleaves human pro‐MSP at the physiological activation site without further degradation, resulting in biologically active MSP, as measured by the chemotactic response and MSP‐induced morphological change of peritoneal macrophages. The processing of pro‐MSP by HGFA is 10‐fold more efficient than processing by factor XIa. To search for a role of HGFA in pro‐MSP activation, we analyzed the processing of mouse pro‐MSP in sera from HGFA‐knockout (HGFA−/−) mice. The proform of MSP was the predominant molecular form in the plasma of both wild‐type and HGFA−/− mice. In wild‐type sera, endogenous pro‐MSP was progressively converted to the mature two‐chain form during incubation at 37 °C. However, this conversion was significantly impaired in sera from HGFA−/− mice. The addition of recombinant HGFA to HGFA‐deficient serum restored pro‐MSP convertase activity in a dose‐dependent manner, and a neutralizing antibody to HGFA significantly reduced the conversion of pro‐MSP in wild‐type serum. Moreover, initial infiltration of macrophages into the site of mechanical skin injury was delayed in HGFA−/− mice. We suggest that HGFA is a major serum activator of pro‐MSP.