title: Matriptase is required for the active form of hepatocyte growth factor induced Met, focal adhesion kinase and protein kinase B activation on neural stem/progenitor cell motility.
abstract: Hepatocyte growth factor (HGF) is a chemoattractant and inducer for neural stem/progenitor (NS/P) cell migration. Although the type II transmembrane serine protease, matriptase (MTP) is an activator of the latent HGF, MTP is indispensable on NS/P cell motility induced by the active form of HGF. This suggests that MTP's action on NS/P cell motility involves mechanisms other than proteolytic activation of HGF. In the present study, we investigate the role of MTP in HGF-stimulated signaling events. Using specific inhibitors of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) or focal adhesion kinase (FAK), we demonstrated that in NS/P cells HGF-activated c-Met induces PI3k-Akt signaling which then leads to FAK activation. This signaling pathway ultimately induces MMP2 expression and NS/P cell motility. Knocking down of MTP in NS/P cells with specific siRNA impaired HGF-stimulation of c-Met, Akt and FAK activation, blocked HGF-induced production of MMP2 and inhibited HGF-stimulated NS/P cell motility. MTP-knockdown NS/P cells cultured in the presence of recombinant protein of MTP protease domain or transfected with the full-length wild-type but not the protease-defected MTP restored HGF-responsive events in NS/P cells. In addition to functioning as HGF activator, our data revealed novel function of MTP on HGF-stimulated c-Met signaling activation.
authors.affiliation: Institute of Cellular and Systems Medicine, National Health Research Institutes, 35 Keyan Rd., Zhunan Town, Miaoli County 35053, Taiwan, Republic of China.
authors.forename: Jung-Da
authors.initials: JD
authors.lastname: Fang
authors.affiliation: Institute of Cellular and Systems Medicine, National Health Research Institutes, 35 Keyan Rd., Zhunan Town, Miaoli County 35053, Taiwan, Republic of China. Electronic address: sllee@nhri.org.tw.
authors.forename: Sheau-Ling
authors.initials: SL
authors.lastname: Lee
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051417:Focal Adhesion Kinase 1; D017228:Hepatocyte Growth Factor; D020778:Matrix Metalloproteinase 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; C553307:HGF protein, mouse; C496051:Ptk2 protein, mouse; C485595:matriptase; C522362:Mmp2 protein, mouse
keywords: Hepatocyte growth factor; Migration; Neural stem cell; Protein kinase signaling; Transmembrane serine protease