Etk/BMX, a member of the Btk family of tyrosine kinases, is highly expressed in cells with great migratory potential, including endothelial cells and metastatic carcinoma cell lines. Here, we present evidence that Etk is involved in integrin signalling and promotes cell migration. The activation of Etk by extracellular matrix proteins is regulated by FAK through an interaction between the PH domain of Etk and the FERM domain of FAK. The lack of Etk activation by extracellular matrix in FAK-null cells could be restored by co-transfection with wild-type FAK. Disrupting the interaction between Etk and FAK diminished the cell migration promoted by either kinase. Furthermore, inhibiting Etk expression in metastatic carcinoma cell lines with an antisense oligonucleotide blocks integrin-mediated migration of these cells. Taken together, our data indicate the essential role of the interaction of the PH domain of Etk and the FERM domain of FAK in integrin signalling.
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ACKNOWLEDGEMENTS We thank L. Higgins for mass spectrometry data analysis, J. McCarthy and J. Iida for providing reagents and advice throughout the study, D. Ilic and C. Damsky for providing FAK-null cells, and D. Schlaepfer, J. DeLarco and X. Zhang for helpful discussion. This work was supported by grants from Minnesota Medical Foundation, AHA (9960296Z) and NIH (CA85380) to Y.Q. Correspondence and requests for materials should be addressed to Y.Q.
Copyright 2007 Elsevier B.V., All rights reserved.