title: TMPRSS4 induces cancer cell invasion through pro-uPA processing.
abstract: TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates cancer cell invasion, epithelial-mesenchymal transition, and metastasis and that increased TMPRSS4 expression correlates with colorectal cancer progression. We also demonstrated that TMPRSS4 upregulates urokinase-type plasminogen activator (uPA) gene expression to induce cancer cell invasion. However, it remains unknown how proteolytic activity of TMPRSS4 contributes to invasion. In this study, we report that TMPRSS4 directly converted inactive pro-uPA into the active form through its proteolytic activity. Analysis of conditioned medium from cells overexpressing TMPRSS4 demonstrated that the active TMPRSS4 protease domain is released from the cells and is associated with the plasma membrane. Furthermore, TMPRSS4 could increase pro-uPA-mediated invasion in a serine proteolytic activity-dependent manner. These observations suggest that TMPRSS4 is an upstream regulator of pro-uPA activation. This study provides valuable insights into the proteolytic function of TMPRSS4 as well as mechanisms for the control of invasion.
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Min
authors.affiliation: Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Republic of Korea.
authors.forename: Myung Kyu
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea. Electronic address: jwl@snu.ac.kr.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Republic of Korea. Electronic address: semikim@kribb.re.kr.
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase
keywords: Invasion; Processing; TMPRSS4; uPA