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C‐terminal Src kinase controls development and maintenance of mouse squamous epithelia
Author(s) -
Yagi Reiko,
Waguri Satoshi,
Sumikawa Yasuyuki,
Nada Shigeyuki,
Oneyama Chitose,
Itami Satoshi,
Schmedt Christian,
Uchiyama Yasuo,
Okada Masato
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601595
Subject(s) - biology , microbiology and biotechnology , cancer research , cell migration , cell adhesion , proto oncogene tyrosine protein kinase src , kinase , cell , genetics
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‐α. Inhibition of the expression of TNF‐α 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.