title: Tensin-4-dependent MET stabilization is essential for survival and proliferation in carcinoma cells.
abstract: Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with β1-integrin cytoplasmic tail positively regulates β1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland.
authors.forename: Ghaffar
authors.initials: G
authors.lastname: Muharram
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland.
authors.forename: Pranshu
authors.initials: P
authors.lastname: Sahgal
authors.affiliation: Department of Pathology, University of Turku, Turku, 20520, Finland; Department of Pathology, Turku University Hospital, Turku, 20520, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Korpela
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Franceschi
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland.
authors.forename: Riina
authors.initials: R
authors.lastname: Kaukonen
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Clark
authors.affiliation: Institut de Biologie de Lille-UMR8161, CNRS, 59021 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Tulasne
authors.affiliation: Department of Pathology, University of Turku, Turku, 20520, Finland; Department of Pathology, Turku University Hospital, Turku, 20520, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Carpén
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland; Department of Biochemistry and Food Chemistry, University of Turku, 20520, Finland. Electronic address: johanna.ivaska@utu.fi.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000818:Animals; D001665:Binding Sites; D002277:Carcinoma / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000473:pathology*; D004705:Endocytosis; D005260:Female; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D000070876:Tensins
chemical_list: D019012:Integrin beta1; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; C000603371:TNS4 protein, human; D000070876:Tensins; C000603393:Tns4 protein, mouse; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met