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pubmed-article:19456860pubmed:abstractTextMacrophage-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 degrees 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.lld:pubmed
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pubmed-article:19456860pubmed:articleTitleHepatocyte growth factor activator is a serum activator of single-chain precursor macrophage-stimulating protein.lld:pubmed
pubmed-article:19456860pubmed:affiliationSection of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.lld:pubmed
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pubmed-article:19456860pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
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