title: Beta1 integrin cytoplasmic tyrosines promote skin tumorigenesis independent of their phosphorylation.
abstract: β1 integrin tyrosine phosphorylation by oncogenic kinases, such as Src, has been predicted to induce tumorigenesis by disrupting adhesion and modifying integrin signaling. We directly tested this hypothesis by subjecting mice with "nonphosphorylatable" tyrosine-to-phenylalanine substitutions in the conserved β1 cytoplasmic tail NPxY motifs to a model of cutaneous carcinogenesis in the presence or absence of elevated Src activity. We found that hydrophobic phenylalanine substitutions of both tyrosines diminished the binding of tail-interacting proteins, including talins and kindlins, resulting in reduced β1-mediated adhesion, focal adhesion kinase (FAK) signaling, and epidermal progenitor cell-derived skin tumors. However, increased Src activity drove tumor formation independent of the phenylalanine substitutions by enhancing FAK activity, which in turn maintained the epidermal progenitor state and blocked keratinocyte differentiation. We conclude that a Src/FAK signaling unit inhibits differentiation to promote tumorigenesis downstream of β1 integrin and independent of β1 integrin tyrosine phosphorylation.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute for Biochemistry, 82152 Martinsried, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meves
authors.forename: Tamar
authors.initials: T
authors.lastname: Geiger
authors.forename: Sara
authors.initials: S
authors.lastname: Zanivan
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D003593:Cytoplasm / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D007553:Isotope Labeling; D015603:Keratinocytes / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D050505:Mutant Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D019000:Phosphotyrosine; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases