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Molecular and Cellular Biology, January 2008, p. 201-214, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01324-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Spatial and Temporal Regulation of Focal Adhesion Kinase Activity in Living Cells{triangledown}

Xinming Cai,1 Daniel Lietha,5 Derek F. Ceccarelli,5,{dagger} Andrei V. Karginov,2 Zenon Rajfur,1 Ken Jacobson,1,3 Klaus M. Hahn,2,3 Michael J. Eck,5 and Michael D. Schaller1,3,4*

Department of Cell and Developmental Biology,1 Department of Pharmacology,2 Lineberger Comprehensive Cancer Center,3 Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 021155

Received 23 July 2007/ Returned for modification 21 August 2007/ Accepted 22 October 2007

Focal adhesion kinase (FAK) is an essential kinase that regulates developmental processes and functions in the pathology of human disease. An intramolecular autoinhibitory interaction between the FERM and catalytic domains is a major mechanism of regulation. Based upon structural studies, a fluorescence resonance energy transfer (FRET)-based FAK biosensor that discriminates between autoinhibited and active conformations of the kinase was developed. This biosensor was used to probe FAK conformational change in live cells and the mechanism of regulation. The biosensor demonstrates directly that FAK undergoes conformational change in vivo in response to activating stimuli. A conserved FERM domain basic patch is required for this conformational change and for interaction with a novel ligand for FAK, acidic phospholipids. Binding to phosphatidylinositol 4,5-bisphosphate (PIP2)-containing phospholipid vesicles activated and induced conformational change in FAK in vitro, and alteration of PIP2 levels in vivo changed the level of activation of the conformational biosensor. These findings provide direct evidence of conformational regulation of FAK in living cells and novel insight into the mechanism regulating FAK conformation.

* Corresponding author. Mailing address: Department of Cell & Developmental Biology, 534 Taylor Hall, CB 7090, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-0391. Fax: (919) 966-1856. E-mail: crispy4{at}med.unc.edu

{triangledown} Published ahead of print on 27 October 2007.

{dagger} Present address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.

Molecular and Cellular Biology, January 2008, p. 201-214, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01324-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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