Direct stimulation of Bruton's tyrosine kinase by Gq-protein α-subunit

Abstract

Heterotrimeric guanine-nucleotide-binding regulatory proteins (G proteins) transduce signals from a wide variety of cell-surface receptors to generate physiological responses¹. Protein-tyrosine kinases are another group of critical cellular signal transducers and their malfunction often leads to cancer². Although activation of G-protein-coupled receptors can elicit rapid stimulation of cellular protein-tyrosine phosphorylation³, the mechanism used by G proteins to activate protein-tyrosine kinases is unclear. Here we show that the purified α-subunit of the G_q class of G proteins (Gαq) directly stimulates the activity of a purified non-receptor kinase, Bruton's tyrosine kinase (Btk)⁴, whereas purified α-subunits from G_i1, G_O or G_z proteins do not. Gαq can also activate Btk in vivo. Furthermore, in Btk-deficient cells, stimulation of another kinase, a p38 MAP kinase, by Gq-coupled receptors is blocked. Our results demonstrate that certain protein-tyrosine kinases can be direct effectors of G proteins.