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

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Abstract
Many receptors for neuropeptides and hormones are coupled with the heterotrimeric Gi protein, which activates the p42/44 mitogen-activated protein kinase (ERK/MAPK) cascade through both the α- and βγ-subunits of Gi (1,​ 2,​ 3). The βγ-subunit activates the ERK/MAPK cascade through tyrosine kinase4,5,6. Constitutively active Gαi2 (gip2) isolated from adrenal and ovarian tumours7,8 transforms Rat-1 fibroblasts and also activates the ERK/MAPK cascade by an unknown mechanism9,10. The ERK/MAPK pathway is activated by Ras, and is inhibited when the low-molecular-mass GTP-binding protein Rap1 antagonizes Ras function11. Here we show that a novel isoform of Rap1 GTPase-activating protein, called rap1GAPII, binds specifically to the α-subunits of the Gi family of heterotrimeric G-proteins. Stimulation of the Gi-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 α-subunit of Gi activates the Ras-ERK/MAPK mitogenic pathway by membrane recruitment of rap1GAPII and reduction of GTP-bound Rap1.