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The G protein Gα12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain

Nature volume 395, pages 808–813 (1998)Cite this article

Abstract

Heterotrimeric guanine-nucleotide-binding proteins (G proteins) are signal transducers that relay messages from many receptors on the cell surface to modulate various cellular processes1,2,3,4. The direct downstream effectors of G proteins consist of the signalling molecules that are activated by their physical interactions with a Gα or Gβγ subunit. Effectors that interact directly with Gα12 G proteins have yet to be identified5,6. Here we show that Gα12 binds directly to, and stimulates the activity of, Bruton's tyrosine kinase (Btk) and a Ras GTPase-activating protein, Gap1m, in vitro and in vivo. Gα12 interacts with a conserved domain, composed of the pleckstrin-homology domain and the adjacent Btk motif, that is present in both Btk and Gap1m. Our results are, to our knowledge, the first to identify direct effectors for Gα12 and to show that there is a direct link between heterotrimeric and monomeric G proteins.

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Figure 1: Stimulation of Btk kinase activity by Gα12.
Figure 2: Gα12 association with Btk in vitro.
Figure 3: Association of Gα12 with Btk in vivo and in vitro.
Figure 4: Stimulation of Gap1m activity by Gα12.
Figure 5: Gα12 association with Gap1m.
Figure 6: Effects of Gα12 on Ras signalling.
Figure 7: Regulation of the activity of Btk and Ras by endogenous thromboxane A2 receptors.

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Acknowledgements

We thank S. Taylor and D. Shalloway for the pGEX-RBD plasmid; M. Liu and M.Simon for the Gα12 plasmid; and M. Gershengorn, L. Levin, W. Lowry and T. Maack for reading the manuscript. Some of the Sf9 cells were cultured in the National Cell Culture Center. This work was supported by grants from the NIH, the NSF, and the American Heart Association. X.-Y.H. is a Beatrice F.Parvin Investigator of the American Heart Association New York City affiliate.

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Authors and Affiliations

  1. Department of Physiology, Cornell University Medical College, 1300 York Avenue, New York, 10021, New York, USA

    Yun Jiang, Wei Ma, Yong Wan & Xin-Yun Huang

  2. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75235, Texas, USA

    Tohru Kozasa

  3. Division of Biochemistry and Cellular Biology, National Institute of Neuroscience, Kodaira, 187, Tokyo, Japan

    Seisuke Hattori

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Correspondence to Xin-Yun Huang.

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Jiang, Y., Ma, W., Wan, Y. et al. The G protein Gα12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature 395, 808–813 (1998). https://doi.org/10.1038/27454

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