title: C-terminal Src kinase controls development and maintenance of mouse squamous epithelia.
abstract: Carboxy-terminal Src kinase (Csk) is a negative regulator of Src family kinases, which play pivotal roles in controlling cell adhesion, migration, and cancer progression. To elucidate the in vivo role of Csk in epithelial tissues, we conditionally inactivated Csk in squamous epithelia using the keratin-5 promoter/Cre-loxP system in mice. The mutant mice developed apparent defects in the skin, esophagus, and forestomach, with concomitant hyperplasia and chronic inflammation. Histology of the mutant epidermis revealed impaired cell-cell adhesion in basal cell layers. Analysis of primary keratinocytes showed that the defective cell-cell adhesion was caused by cytoskeletal remodeling via activation of the Rac1 pathway. Mutant keratinocytes also showed elevated expression of mesenchymal proteins, matrix metalloproteinases (MMPs), and the proinflammatory cytokine TNF-alpha. Inhibition of the expression of TNF-alpha and MMP9 by the anti-inflammatory reagent FK506 could cure the epidermal hyperplasia, suggesting a causal link between inflammation and epidermal hyperplasia. These observations demonstrate that the Src/Csk circuit plays crucial roles in development and maintenance of epithelia by controlling cytoskeletal organization as well as phenotypic conversion linked to inflammatory events.
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Yagi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sumikawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nada
authors.forename: Chitose
authors.initials: C
authors.lastname: Oneyama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itami
authors.forename: Christian
authors.initials: C
authors.lastname: Schmedt
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004947:Esophagus / Q000166:cytology / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D016559:Tacrolimus / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D053555:Keratin-5; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D020782:Matrix Metalloproteinases; D016559:Tacrolimus