C-terminal Src kinase controls development and maintenance of mouse squamous epithelia.
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.
Yagi
Reiko
R
Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Waguri
Satoshi
S
Sumikawa
Yasuyuki
Y
Nada
Shigeyuki
S
Oneyama
Chitose
C
Itami
Satoshi
S
Schmedt
Christian
C
Uchiyama
Yasuo
Y
Okada
Masato
M
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
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