C-terminal Src Kinase Controls Development and Maintenance of Mouse Squamous Epithelia

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2007 Feb 17

PMID 17304209

Citations 18

Authors

Reiko Yagi

Satoshi Waguri

Yasuyuki Sumikawa

Shigeyuki Nada

Chitose Oneyama

Satoshi Itami

Christian Schmedt

Yasuo Uchiyama

Masato Okada

Affiliations

Soon will be listed here.

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.

Citing Articles

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Adam A, Lowery A, Martino N, Alsaffar H, Vincent P PLoS One. 2016; 11(9):e0161975.

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References

Harris K, Shoji I, Cooper E, Kumar S, Oda H, Howley P . Ubiquitin-mediated degradation of active Src tyrosine kinase. Proc Natl Acad Sci U S A. 1999; 96(24):13738-43. PMC: 24134. DOI: 10.1073/pnas.96.24.13738. View

Waschke J, Spindler V, Bruggeman P, Zillikens D, Schmidt G, Drenckhahn D . Inhibition of Rho A activity causes pemphigus skin blistering. J Cell Biol. 2006; 175(5):721-7. PMC: 2064672. DOI: 10.1083/jcb.200605125. View

Nakagawa T, Tanaka S, Suzuki H, Takayanagi H, Miyazaki T, Nakamura K . Overexpression of the csk gene suppresses tumor metastasis in vivo. Int J Cancer. 2000; 88(3):384-91. View

Irby R, Yeatman T . Role of Src expression and activation in human cancer. Oncogene. 2000; 19(49):5636-42. DOI: 10.1038/sj.onc.1203912. View

Takai Y, Sasaki T, Matozaki T . Small GTP-binding proteins. Physiol Rev. 2001; 81(1):153-208. DOI: 10.1152/physrev.2001.81.1.153. View

Tester A, Ruangpanit N, Anderson R, Thompson E . MMP-9 secretion and MMP-2 activation distinguish invasive and metastatic sublines of a mouse mammary carcinoma system showing epithelial-mesenchymal transition traits. Clin Exp Metastasis. 2001; 18(7):553-60. DOI: 10.1023/a:1011953118186. View

Matsumoto T, Jiang J, Kiguchi K, Carbajal S, Rho O, Gimenez-Conti I . Overexpression of a constitutively active form of c-src in skin epidermis increases sensitivity to tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Mol Carcinog. 2002; 33(3):146-55. DOI: 10.1002/mc.10030. View

Fujita Y, Krause G, Scheffner M, Zechner D, Leddy H, Behrens J . Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol. 2002; 4(3):222-31. DOI: 10.1038/ncb758. View

Frame M . Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta. 2002; 1602(2):114-30. DOI: 10.1016/s0304-419x(02)00040-9. View

10.

Fujii Y, Takeuchi H, Tanaka K, Sakuma S, Ohkubo Y, Mutoh S . Effects of FK506 (tacrolimus hydrate) on chronic oxazolone-induced dermatitis in rats. Eur J Pharmacol. 2002; 456(1-3):115-21. DOI: 10.1016/s0014-2999(02)02554-2. View

11.

Coussens L, Werb Z . Inflammation and cancer. Nature. 2002; 420(6917):860-7. PMC: 2803035. DOI: 10.1038/nature01322. View

12.

Hsia D, Mitra S, Hauck C, Streblow D, Nelson J, Ilic D . Differential regulation of cell motility and invasion by FAK. J Cell Biol. 2003; 160(5):753-67. PMC: 2173366. DOI: 10.1083/jcb.200212114. View

13.

Nimnual A, Taylor L, Bar-Sagi D . Redox-dependent downregulation of Rho by Rac. Nat Cell Biol. 2003; 5(3):236-41. DOI: 10.1038/ncb938. View

14.

Bates R, Mercurio A . Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell. 2003; 14(5):1790-800. PMC: 165077. DOI: 10.1091/mbc.e02-09-0583. View

15.

Matsumoto T, Jiang J, Kiguchi K, Ruffino L, Carbajal S, Beltran L . Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis. Cancer Res. 2003; 63(16):4819-28. View

16.

Ito H, Gardner-Thorpe J, Zinner M, Ashley S, Whang E . Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness. Surgery. 2003; 134(2):221-6. DOI: 10.1067/msy.2003.224. View

17.

Rengifo-Cam W, Konishi A, Morishita N, Matsuoka H, Yamori T, Nada S . Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis. Oncogene. 2004; 23(1):289-97. DOI: 10.1038/sj.onc.1207041. View

18.

Yu H, Jove R . The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 2004; 4(2):97-105. DOI: 10.1038/nrc1275. View

19.

Thomas R, Schmedt C, Novelli M, Choi B, Skok J, Tarakhovsky A . C-terminal SRC kinase controls acute inflammation and granulocyte adhesion. Immunity. 2004; 20(2):181-91. DOI: 10.1016/s1074-7613(04)00023-8. View

20.

Hunter T, Sefton B . Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Natl Acad Sci U S A. 1980; 77(3):1311-5. PMC: 348484. DOI: 10.1073/pnas.77.3.1311. View