The G protein Gα12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain

Heterotrimeric guanine-nucleotide-binding proteins (G proteins) are signal transducers that relay messages from many receptors on the cell surface to modulate various cellular processes(1-4). The direct downstream effecters of G proteins consist of the signalling molecules that are activated by their physical interactions with a G alpha or G beta gamma subunit. Effecters that interact directly with G alpha 12 G, proteins have yet to be identified(5,6). Here we show that G alpha 12 binds directly to, and stimulates the activity of, Bruton's tyrosine kinase (Btk) and a Res GTPase-activating protein, Gap1(m), in vitro and in; vivo. G alpha 12 interacts with a conserved domain, composed of the pleckstrin-homology domain and the adjacent Btk motif, that is present in both Btk and Gap1(m). Our results are, to our knowledge, the first to identify direct effecters for G alpha 12 and to show that there is a direct link between heterotrimeric and monomeric G proteins.