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 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.
Kawaguchi
Makiko
M
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
Orikawa
Hiroshi
H
Baba
Takashi
T
Fukushima
Tsuyoshi
T
Kataoka
Hiroaki
H
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D044967:Serum / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017228:Hepatocyte Growth Factor; D007610:Kallikreins; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C082332:macrophage stimulating protein; C081092:HGF activator; C400147:KLK5 protein, human; C120801:kallikrein 4