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 (1–3). 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.
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Acknowledgements
We thank M. E. Mendelsohn, R. Ingham, S. Hattori and W. Hall for helpful discussions, and M. Sasada, F. Kanda, F. Ohba, S. Yamashita, N. Otsuka and K. Okuda for technical assistance. Supported by grants from the Ministry of Health and Welfare, from the Ministry of Education, Science, Sports, and Culture, and from the Human Science Foundation, Japan.
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Mochizuki, N., Ohba, Y., Kiyokawa, E. et al. Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with Gαi. Nature 400, 891–894 (1999). https://doi.org/10.1038/23738
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DOI: https://doi.org/10.1038/23738
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