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G2A is an oncogenic G protein-coupled receptor

Oncogene volume 19, pages 3866–3877 (2000)Cite this article

Abstract

G2A is a heptahelical cell surface protein that has recently been described as a potential tumor suppressor, based on its ability to counteract transformation of pre-B cells and fibroblasts by Bcr-Abl, an oncogenic tyrosine kinase. We have isolated cDNAs encoding G2A in the course of screening libraries for clones that cause oncogenic transformation of NIH3T3 fibroblasts. When expressed at high levels in NIH3T3 cells by retroviral transduction, G2A induced a full range of phenotypes characteristic of oncogenic transformation, including loss of contact inhibition, anchorage-independent survival and proliferation, reduced dependence on serum, and tumorigenicity in mice. When expressed by transfection, G2A greatly enhanced the ability of a weakly oncogenic form of Raf-1 to transform NIH3T3 cells. These results demonstrate that G2A is potently oncogenic both on its own and in cooperation with another oncogene. Expression of G2A in fibroblasts and endothelial cells resulted in changes in cell morphology and cytoskeleton structure that were equivalent to those induced by the G protein subunit Gα13. Transformation of NIH3T3 cells via G2A expression was completely suppressed by co-expression of LscRGS, a GTPase activating protein that suppresses signaling by Gα12 and Gα13. Hyperactivity of Gα12 or Gα13 has previously been shown to result in activation of Rho GTPases. G2A expression resulted in activation of Rho, and transformation via G2A was suppressed by a dominant negative form of RhoA. These results indicate that G2A may be directly coupled to Gα13, and that it is the activation of this Rho-activating Gα protein which is responsible for the ability of G2A to transform fibroblasts.

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Acknowledgements

We thank Henry Bourne for providing expression constructs for activated Gα12, Gα13 and Gαq, Warren Pear for providing the BOSC 23 cells and advice on using them, Carol Martin and Que Lambert for technical assistance, and Jennifer Parrish for preparation of figures. Our research was supported by a grant from the Medical Research Council of Canada to R Kay and by grants from the National Institutes of Health (CA42978, CA55008 and CA63071) to CJ Der.

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Author notes

  1. Irene E Zohn

    Present address: Laboratory of Molecular Embryology, Rockefeller University, New York, 10021, NY, USA

  2. Marc Symons

    Present address: The Picower Institute for Medical Research, 350 Community Drive, Manhasset, 11030, NY, USA

  3. Irene E Zohn and Mark Klinger: The first two authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7038, NC, USA

    Irene E Zohn & Channing J Der

  2. Department of Cell Biology and Anatomy, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7038, NC, USA

    Magdalena Chrzanowska-Wodnicka

  3. Curriculum in Genetics and Molecular Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7038, NC, USA

    Channing J Der

  4. Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7038, NC, USA

    Channing J Der

  5. Department of Medical Genetics, University of British Columbia, and Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 4E6, Canada

    Mark Klinger, Xantha Karp, Heather Kirk & Robert J Kay

  6. Onyx Pharmaceuticals, 3031 Research Drive, Building A, Richmond, California, 94806, CA, USA

    Marc Symons

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Zohn, I., Klinger, M., Karp, X. et al. G2A is an oncogenic G protein-coupled receptor. Oncogene 19, 3866–3877 (2000). https://doi.org/10.1038/sj.onc.1203731

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