Direct stimulation of Bruton's tyrosine kinase by G(q)-protein alpha-subunit

Heterotrimeric guanine-nucleotide-binding regulatory proteins (G proteins) transduce signals from a wide variety of cell-surface receptors to generate physiological responses(1). Protein-tyrosine kinases are another group of critical cellular signal transducers and their malfunction often leads to cancer(2). Although activation of G-protein-coupled receptors can elicit rapid stimulation cellular protein-tyrosine phosphorylation(3), the mechanism used by G proteins to activate protein-tyrosine kinases is unclear. Here we show that the purified alpha-subunit of the G(q) class of G proteins (G alpha q) directly stimulates the activity of a purified non-receptor kinase, Bruton's tyrosine kinase (Btk)(4), whereas purified alpha-subunits from G(i1), G(0) or G(z) proteins do not, G alpha q 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 effecters of G proteins.