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J. Biol. Chem., Vol. 279, Issue 8, 6824-6833, February 20, 2004

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The Kindler Syndrome Protein Is Regulated by Transforming Growth Factor- and Involved in Integrin-mediated Adhesion^*

Susanne Kloeker, Michael B. Major, David A. Calderwood, Mark H. Ginsberg, David A. Jones, and Mary C. Beckerle¶||

From the Departments of Oncological Sciences and ^¶Biology, Huntsman Cancer Institute, Salt Lake City, Utah 84112-5550 and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Transforming growth factor-1 (TGF-1) contributes to tumor invasion and cancer progression by increasing the motility of tumor cells. To identify genes involved in TGF--mediated cell migration, the transcriptional profiles of human mammary epithelial cells (HMEC) treated with TGF- were compared with untreated cells by cDNA microarray analysis. One gene up-regulated by TGF- was recently named kindlerin (Jobard, F., Bouadjar, B., Caux, F., Hadj-Rabia, S., Has, C., Matsuda, F., Weissenbach, J., Lathrop, M., Prud'homme, J. F., and Fischer, J. (2003) Hum. Mol. Genet. 12, 925–935). This gene is significantly overexpressed in some cancers (Weinstein, E. J., Bourner, M., Head, R., Zakeri, H., Bauer, C., and Mazzarella, R. (2003) Biochim. Biophys. Acta 1637, 207–216), and mutations in this gene lead to Kindler syndrome, an autosomal-recessive genodermatosis. TGF- stimulation of HMEC resulted in a marked induction of kindlerin RNA, and Western blotting demonstrated a corresponding increase in protein abundance. Kindlerin displays a putative FERM (four point one ezrin radixin moesin) domain that is closely related to the sequences in talin that interact with integrin subunit cytoplasmic domains. The critical residues in the talin FERM domain that mediate integrin binding show a high degree of conservation in kindlerin. Furthermore, kindlerin is recruited into a molecular complex with the _1A and ₃ integrin cytoplasmic domains. Consistent with these biochemical findings, kindlerin is present at focal adhesions, sites of integrin-rich, membrane-substratum adhesion. Additionally, kindlerin is required for normal cell spreading. Taken together, these data suggest a role for kindlerin in mediating cell processes that depend on integrins.

Received for publication, July 22, 2003 , and in revised form, November 19, 2003.

^* This work was supported by National Research Service Award F32 20457 (to S. K.), the Multidisciplinary Cancer Research Training Program Grant T32 CA93247 (to S. K.), the Huntsman Cancer Foundation, the Willard L. Eccles Foundation, National Institutes of Health Grants GM50877 (to M. C. B.) and HL48728 (to M. H. G.), the American Heart Association Scientist Development grant (to D. A. C.), and the University of Utah DNA-Peptide Facility and Sequencing Facility Technical Support Grant CA42014. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Huntsman Cancer Institute, 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112-5550. Tel.: 801-581-4485; Fax: 801-581-2175; E-mail: mary.beckerle{at}hci.utah.edu.

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