A novel c-Src activation mechanism by integrin β3. (A) The initial contact. The c-Src kinase is depicted in its inactive form. (B) A putative transition state in which the c-Src is primed by integrin β3. The intramolecular interactions between the SH3, SH2, SH2-linker, and kinase domain are thought to be important for the enzymatic activity. As suggested by the complexes of SH3:RGT and c-Src:β3, the binding of the RGT peptide could disrupt these intramolecular constraints, leading to the disengagement of Trp260 and “C”-helix. (C) As a result, the enzyme is primed for further activations, including the phosphorylation of Tyr416 in the active site in the kinase domain, a process that could be facilitated by integrin microclustering, autophosphorylation,19 and dephosphorylation of Tyr527 regulated by the tyrosine phosphatases and Csk kinase.19,35
