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

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

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

Transforming growth factor-β1 (TGF-β1) contributes to tumor invasion and cancer progression by increasing the motility of tumor cells. To identify genes involved in TGF-β-mediated cell migration, the transcriptional profiles of human mammary epithelial cells (HMEC) treated with TGF-β were compared with untreated cells by cDNA microarray analysis. One gene up-regulated by TGF-β 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-β 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 β 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 β1A and β3 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.

Original languageEnglish
Pages (from-to)6824-6833
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number8
DOIs
StatePublished - Feb 20 2004

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