Transforming growth factor-beta1 (TGF-beta1) contributes to
tumor invasion and
cancer progression by increasing the motility of
tumor cells. To identify genes involved in
TGF-beta-mediated cell migration, the transcriptional profiles of human mammary epithelial cells (HMEC) treated with
TGF-beta were compared with untreated cells by
cDNA microarray analysis. One gene up-regulated by
TGF-beta 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-beta 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 beta 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 beta1A and
beta3 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.