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Macrophage-stimulating protein (MSP) is a plasma protein that circu-lates as a single-chain proform. It acquires biological activity after prote-olytic cleavage at the Arg483–Val484 bond, a process in which serum and cell surface serine proteinases have been implicated. | ỊFEBS Journal Hepatocyte growth factor activator is a serum activator of single-chain precursor macrophage-stimulating protein Makiko Kawaguchi Hiroshi Orikawa Takashi Baba Tsuyoshi Fukushima and Hiroaki Kataoka Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki Japan Keywords activation hepatocyte growth factor activator macrophage-stimulating protein recepteur d origine nantais RON serum Correspondence H. Kataoka Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki 5200 Kihara Kiyotake Miyazaki 889-1692 Japan Fax 81 985 85 6003 Tel 81 985 85 2809 E-mail mejina@med.miyazaki-u.ac.jp Received 14 February 2009 revised 7 April 2009 accepted 22 April 2009 doi 10.1111 j.1742-4658.2009.07070.x 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
