Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i)

Abstract:

:Many receptors for neuropeptides and hormones are coupled with the heterotrimeric G(i) protein, which activates the p42/44 mitogen-activated protein kinase (ERK/MAPK) cascade through both the alpha- and betagamma-subunits of G(i). The betagamma-subunit activates the ERK/MAPK cascade through tyrosine kinase. Constitutively active G(alpha)i2 (gip2) isolated from adrenal and ovarian tumours transforms Rat-1 fibroblasts and also activates the ERK/MAPK cascade by an unknown mechanism. The ERK/MAPK pathway is activated by Ras, and is inhibited when the low-molecular-mass GTP-binding protein Rap1 antagonizes Ras function. Here we show that a novel isoform of Rapl 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.

journal_name

Nature

journal_title

Nature

authors

Mochizuki N,Ohba Y,Kiyokawa E,Kurata T,Murakami T,Ozaki T,Kitabatake A,Nagashima K,Matsuda M

doi

10.1038/23738

keywords:

subject

Has Abstract

pub_date

1999-08-26 00:00:00

pages

891-4

issue

6747

eissn

0028-0836

issn

1476-4687

journal_volume

400

pub_type

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