Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition.
Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. In contrast, substitution of Tyr194 with Glu (Y194E substitution) leads to constitutive activation of FAK. The phosphorylation of FAK on Tyr194 may cause conformational changes in the FERM domain, which disrupts the intramolecular inhibitory interaction between the FERM and kinase domains of FAK. Moreover, substitution of the basic residues in the (216)KAKTLRK(222) patch in the FERM domain with Ala antagonizes the effect of the Y194E substitution on FAK activation, thus suggesting that the interactions between the phosphorylated Tyr194 and the basic resides in the (216)KAKTLRK(222) patch may allow FAK to be activated through relief of its autoinhibition. Collectively, this study provides the first example to explain how FAK is activated by receptor tyrosine kinases.
Chen
T-H
TH
Department of Life Science, National Chung Hsing University, Taichung, Taiwan. hcchen@nchu.edu.tw
Chan
P-C
PC
Chen
C-L
CL
Chen
H-C
HC
D000595:Amino Acid Sequence; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; D008565:Membrane Proteins; D008840:Microfilament Proteins; D019859:Proto-Oncogene Proteins c-met; D017479:Receptors, Platelet-Derived Growth Factor; D014443:Tyrosine; D000099149:Ezrin; C071058:moesin; C071776:radixin; C496050:PTK2 protein, human