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

Author

Listed:
  • Naoki Mochizuki

    (Research Institute, International Medical Center of Japan)

  • Yusuke Ohba

    (Research Institute, International Medical Center of Japan)

  • Etsuko Kiyokawa

    (National Institute of Infectious Diseases)

  • Takeshi Kurata

    (National Institute of Infectious Diseases)

  • Takeshi Murakami

    (Departments of Cardiovascular Medicine)

  • Takefumi Ozaki

    (Departments of Cardiovascular Medicine)

  • Akira Kitabatake

    (Departments of Cardiovascular Medicine)

  • Kazuo Nagashima

    (Pathology, Hokkaido University School of Medicine)

  • Michiyuki Matsuda

    (Research Institute, International Medical Center of Japan)

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.

Suggested Citation

  • Naoki Mochizuki & Yusuke Ohba & Etsuko Kiyokawa & Takeshi Kurata & Takeshi Murakami & Takefumi Ozaki & Akira Kitabatake & Kazuo Nagashima & Michiyuki Matsuda, 1999. "Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with Gαi," Nature, Nature, vol. 400(6747), pages 891-894, August.
    • Handle: RePEc:nat:nature:v:400:y:1999:i:6747:d:10.1038_23738
    DOI: 10.1038/23738
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