Biochem. J. (2003) 369
(407–416) (Printed in Great Britain)
Site-specific phosphorylation of platelet focal adhesion kinase by low-density lipoprotein
Ingrid A.M. RELOU*†1 , Liane A.B. BAX* , Herman J.M. VAN RIJN† and Jan-Willem N. AKKERMAN*
*Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands, and †Department of Clinical Chemistry, University Medical Center Utrecht and Institute for Biomembranes, University of Utrecht, The Netherlands
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase implicated in signalling pathways mediated by integrins and G-protein-coupled receptors (GPCRs). Upon stimulation FAK is phosphorylated on six tyrosine residues. Here we report the site-specific phosphorylation by low-density lipoprotein (LDL), which is known to induce integrin-independent FAK phosphorylation, and compare this with the effect of thrombin, which phosphorylates FAK via integrin aIIbb3. Stimulation with LDL reveals (i) a major role for Tyr-925 phosphorylation which surpasses the phosphorylation of the other residues, including Tyr-397, in rate and extent, (ii) aIIbb3-independent phosphorylation of Tyr-925 and Tyr-397, and (iii) complex formation between FAK and the Src-kinase Fgr but not with c-Src. These patterns differ profoundly from those induced by thrombin. LDL-induced phosphorylation of Tyr-925 and Tyr-397 was inhibited by 60–75% by receptor-associated protein, an inhibitor of members of the LDL receptor family. Thus these findings reveal a novel mechanism of FAK phosphorylation by signalling cascades involving a member of the LDL receptor family.
Key words: focal adhesion kinase (FAK), Fgr, LRP8, Src.
Abbreviations used: apo, apolipoprotein; FAK, focal adhesion kinase; GPCR, G-protein-coupled receptor; LDL, low-density lipoprotein; PAR, protease-activated receptor; PP-1, pyrazolopyrimidine 1; RAP, receptor-associated protein.
1To whom correspondence should be addressed (e-mail i.relou@azu.nl).
Received 13 March 2002/10 October 2002; accepted 18 October 2002
Published as BJ Immediate Publication 18 October 2002, DOI 10.1042/BJ20020410
The Biochemical Society, London ©
2003
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