Akt Binds to and Phosphorylates Phospholipase C-γ1 in Response to Epidermal Growth Factor

摘要

Both phospholipase (PL) C-γ1 and Akt (protein kinase B; PKB) are signaling proteins that play significant roles in the intracellular signaling mechanism used by receptor tyrosine kinases, including epidermal growth factor (EGF) receptor (EGFR). EGFR activates PLC-γ1 directly and activates Akt indirectly through phosphatidylinositol 3-kinase (PI3K). Many studies have shown that the PLC-γ1 pathway and PI3K–Akt pathway interact with each other. However, it is not known whether PLC-γ1 binds to Akt directly. In this communication, we identified a novel interaction between PLC-γ1 and Akt. We demonstrated that the interaction is mediated by the binding of PLC-γ1 Src homology (SH) 3 domain to Akt proline-rich motifs. We also provide a novel model to depict how the interaction between PLC-γ1 SH3 domain and Akt proline-rich motifs is dependent on EGF stimulation. In this model, phosphorylation of PLC-γ1 Y783 by EGF causes the conformational change of PLC-γ1 to allow the interaction of its SH3 domain with Akt proline-rich motifs. Furthermore, we showed that the interaction between PLC-γ1 and Akt resulted in the phosphorylation of PLC-γ1 S1248 by Akt. Finally, we showed that the interaction between PLC-γ1 and Akt enhanced EGF-stimulated cell motility.