title: Activation of MMP-9 by membrane type-1 MMP/MMP-2 axis stimulates tumor metastasis.
abstract: An artificial receptor for proMMP-9 was created by fusing tissue inhibitor of MMP-1 (TIMP-1) with type II transmembrane mosaic serine protease (MSP-T1). Expression of MSP-T1 in 293T cells induced binding of proMMP-9, which was processed by MMP-2 activated by membrane type 1 MMP (MT1-MMP). HT1080 cells transfected with the MSP-T1 gene produced activated MMP-9 in collagen gel, and addition of proMMP-2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT1080 cells with concanavalin A in the presence of exogenous proMMP-2 induced activation of not only proMMP-2 but also proMMP-9. Knockdown of MT1-MMP or TIMP-2 expression with siRNA suppressed activation of both proMMP-2 and proMMP-9. Transfection of TIMP-1 siRNA suppressed cell binding and activation of proMMP-9, but not proMMP-2 activation. Knockdown of a disintegrin and metalloproteinase 10 (ADAM10) expression reduced cell binding and processing of proMMP-9. These results suggest that proMMP-9, which binds to a receptor complex containing TIMP-1 and ADAM10, is activated by the MT1-MMP/MMP-2 axis, and MMP-9 thus activated stimulates cellular proteolysis and metastasis.
authors.affiliation: Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Zichen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Takino
authors.affiliation: Central Research Resource Branch, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D003208:Concanavalin A / Q000494:pharmacology; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D003208:Concanavalin A; D019716:Tissue Inhibitor of Metalloproteinase-2; D053829:Amyloid Precursor Protein Secretases; D012697:Serine Endopeptidases; C055645:hepsin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: Activation; MMP-2; MMP-9; MT1-MMP; TIMP-1