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First published online 10 February 2009
doi: 10.1242/jcs.028738

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Dynamic conformational changes in the FERM domain of FAK are involved in focal-adhesion behavior during cell spreading and motility

¹ Molecular Biology of Neuronal Signals, Max-Planck Institute of Experimental Medicine, 37075 Göttingen, Germany
² Department of Neuro- and Sensory Physiology, University Medicine Göttingen, 37073 Göttingen, Germany
³ Cellular Biophysics, European Neuroscience Institute, 37073 Göttingen, Germany
⁴ Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
⁵ DFG Research Center for Molecular Physiology of the Brain (CMPB), 37073 Göttingen, Germany
⁶ Laboratory of Cellular Dynamics, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany

^* Author for correspondence (e-mail: gbunt{at}gwdg.de)

Accepted 6 November 2008

Focal adhesion kinase (FAK) controls cellular adhesion and motility processes by its tight link to integrin- and extracellular-matrix-mediated signaling. To explore the dynamics of the regulation of FAK, we constructed a FRET-based probe that visualizes conformational rearrangements of the FERM domain of FAK in living cells. The sensor reports on an integrin-mediated conformational change in FAK following cellular adhesion. The perturbation is kinase-independent and involves the polybasic KAKTLR sequence in the FERM domain. It is manifested by an increased FRET signal and is expressed primarily in focal adhesions, and to a lesser extent in the cytoplasm. The conformational change in the FERM domain of FAK is observed in two consecutive phases during spreading – early and late – and is enriched in fully adhered motile cells at growing and sliding peripheral focal-adhesion sites, but not in stable or retracting focal adhesions. Inhibition of the actomyosin system indicates the involvement of tension signaling induced by Rho-associated kinase, rather than by myosin light-chain kinase, in the modulation of the FERM response. We conclude that the heterogeneous conformation of the FERM domain in focal adhesions of migrating cells reflects a complex regulatory mechanism for FAK that appears to be under the influence of cellular traction forces.

Key words: FERM conformation, FAK, FRET, Migration, ROCK, Force

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