Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with Gαi

Many receptors for neuropeptides and hormones are coupled with the heterotrimeric G(i) protein, which activates the p42/44 mitogen-activated protein kinase (ERK/MAPE;) cascade through both the alpha- and beta gamma-subunits of G(i) (refs 1-3). The beta gamma-subunit activates the ERK/MAPK cascade through tyrosine kinase(4-6). Constitutively active G alpha(i2) (gip2) isolated from adrenal and ovarian tumours(7,8) transforms Rat-1 fibroblasts and also activates the ERK/MAPK cascade by an unknown mechanism(9,10). The ERK/MAPK pathway is activated by Ras, and is inhibited when the low-molecular-mass GTP-binding protein Rap1 antagonizes pas function(11). Here we show that a novel isoform of Rap1 GTPase-activating protein, called rap1GAPII, binds specifically to the alpha-subunits of the G(i) family of heterotrimeric G-proteins. Stimulation of the G(i)-coupled m2-muscarinic receptor translocates rap1GAPII from the cytosol to the membrane and decreases the amount of GTP-bound Rap1. This decrease in GTP-bound Rap1 activates ERK/MAPK. Thus, the alpha-subunit of G(i) activates the Ras-ERK/MAPK mitogenic pathway by membrane recruitment of rap1GAPII and reduction of GTP-bound Rap1.