Src tyrosine kinase is a novel direct effector of G proteins

Heterotrimeric G proteins transduce signals from cell surface receptors to modulate the activity of cellular effecters. Src, the product of the first characterized proto-oncogene and the first identified protein tyrosine kinase, plays a critical role in the signal transduction of G protein-coupled receptors. However, the mechanism of biochemical regulation of Src by G proteins is not known. Here we demonstrate that G alpha s and G alpha i, but neither G alpha q, G alpha 12 nor G beta gamma, directly stimulate the kinase activity of downregulated c-Src. G alpha s and G alpha i similarly modulate Hck, another member of Src-family tyrosine kinases. G alpha s and G alpha i bind to the catalytic domain and change the conformation of Src, leading to increased accessibility of the active site to substrates. These data demonstrate that the Src family tyrosine kinases are direct effecters of G proteins.