Epidermal growth factor receptor (EGFR) is a 170 kDa trasmembrane protein, activation of which results in its dimerization and tyrosine autophosphorylation and subsequent recruitment of downstream signaling molecules that mediate cell proliferation, regeneration, migration, endocytosis and clustering. Focal adhesion kinase (FAK) is an essential regulator of growth factor receptors that function as actin cytoskeleton-related network of signaling transduction proteins, including Src, cdc42, Rac1 and RhoA. Dimerization and clustering are the most important procedures in receptor tyrosine kinase activation of signaling transduction, which are modulated by actin cytoskeleton remodeling. However, molecular mechanisms underlying dimerization and clustering of receptor molecules are still unclarified. In this study, we investigated howan EGF-derived peptide called YAC tripeptide induces EGFR dimerization. Our study presents that YAC tripeptide induces the physical interaction among EGFR-Grb2-SOS-FAK-cSrc complex, which leads to FAK phosphorylation. Transfection of MCF-7 cells with either dominant-negative FAK or FAK siRNA reducedEGFR dimerization and subsequent endocytosis of EGFR. YAC tripeptide enhanced the interaction RhoA, Rac1 and cdc42 with FAK.Dominant-negative RhoA, Rac1 and cdc42 abrogated YAC tripeptide-inducedendocytosis of EGFR. Moreover, it induced FAK-mediated activation of Rac1-Wave2-Arp2 and RhoA-Rock2-Ezrin axis. These results demonstrate that YAC tripeptide enhances EGFR clustering through FAK-mediatedRac1-Wave2-Arp2 and RhoA-Rock2-Ezrin signaling axis.
key words : Clustering, Dimerization, EGFR, FAK, YAC tripeptide