Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
195,33 € per year
only 16,28 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout




Similar content being viewed by others
References
Qiu, Y., Robinson, D., Pretlow, T. G. & Kung, H. J. Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3′-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc. Natl Acad. Sci. USA 95, 3644–3649 (1998).
Tamagnone, L. et al. BMX, a novel nonreceptor tyrosine kinase gene of the BTK/ITK/TEC/TXK family located in chromosome Xp22.2. Oncogene 9, 3683–3688 (1994).
Rawlings, D. J. & Witte, O. N. The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function. Semin. Immunol. 7, 237–246 (1995).
Xue, L. Y., Qiu, Y., He, J., Kung, H. J. & Oleinick, N. L. Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin. Oncogene 18, 3391–3398 (1999).
Tsai, Y. T. et al. Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation. Mol. Cell. Biol. 20, 2043–2054 (2000).
Gibson, T. J., Hyvonen, M., Musacchio, A., Saraste, M. & Birney, E. PH domain: the first anniversary. Trends Biochem. Sci. 19, 349–353 (1994).
Yao, L. et al. Pleckstrin homology domains interact with filamentous actin. J. Biol. Chem. 274, 19752–19761 (1999).
Parsons, J. T. Integrin-mediated signalling: regulation by protein tyrosine kinases and small GTP-binding proteins. Curr. Opin. Cell Biol. 8, 146–152 (1996).
Giancotti, F. G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).
Chishti, A. H. et al. The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends Biochem. Sci. 23, 281–282 (1998).
Girault, J. A., Labesse, G., Mornon, J. P. & Callebaut, I. The N-termini of FAK and JAKs contain divergent band 4.1 domains. Trends Biochem. Sci. 24, 54–57 (1999).
Sieg, D. J. et al. FAK integrates growth-factor and integrin signals to promote cell migration. Nature Cell Biol. 2, 249–256 (2000).
Stephenson, R. A. et al. Metastatic model for human prostate cancer using orthotopic implantation in nude mice. J. Natl Cancer Inst. 84, 951–957 (1992).
Thompson, E. W. et al. Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J. Cell. Physiol. 150, 534–544 (1992).
Pearson, M. A., Reczek, D., Bretscher, A. & Karplus, P. A. Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 101, 259–270 (2000).
Reiske, H. R. et al. Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. J. Biol. Chem. 274, 12361–1236 (1999).
Ilic, D. et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377, 539–544 (1995).
Cary, L. A., Han, D. C., Polte, T. R., Hanks, S. K. & Guan, J. L. Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration. J. Cell Biol. 140, 211–221 (1998).
Jiang, Y. et al. The G protein G alpha12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature 395, 808–813 (1998).
Johannes, F. J. et al. Bruton's tyrosine kinase (Btk) associates with protein kinase C mu. FEBS Lett 461, 68–72 (1999).
Li, T. et al. Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain. Immunity 2, 451–60 (1995).
Hyvonen, M. & Saraste, M. Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinaemia. EMBO J. 16, 3396–3404 (1997).
Sieg, D. J. et al. Pyk2 and Src-family protein-tyrosine kinases compensate for the loss of FAK in fibronectin-stimulated signaling events but Pyk2 does not fully function to enhance FAK-cell migration. EMBO J. 17, 5933–5947 (1998).
Rawlings, D. J. et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 271, 822–825 (1996).
Andreotti, A. H., Bunnell, S. C., Feng, S., Berg, L. J. & Schreiber, S. L. Regulatory intramolecular association in a tyrosine kinase of the Tec family. Nature 385, 93–97 (1997).
Cary, L. A., Chang, J. F. & Guan, J. L. Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J. Cell Sci. 109, 1787–1794 (1996).
Chen, H. C., Appeddu, P. A., Isoda, H. & Guan, J. L. Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J. Biol. Chem. 271, 26329–26334 (1996).
Zheng, C. et al. Differential regulation of Pyk2 and focal adhesion kinase (FAK). The C-terminal domain of FAK confers response to cell adhesion. J. Biol. Chem. 273, 2384–2389 (1998).
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, R., Kim, O., Li, M. et al. Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nat Cell Biol 3, 439–444 (2001). https://doi.org/10.1038/35074500
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/35074500