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p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities

Oncogene volume 28, pages 1401–1409 (2009)Cite this article

Abstract

DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.

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Acknowledgements

The Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH supported this work. CJD is also supported by an NIH grant (1R01CA129610), and DV was supported by a fellowship from the American Cancer Society.

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Author notes

  1. M Guan

    Present address: 4Current address: Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China.,

Authors and Affiliations

  1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    X-Y Yang, M Guan & N C Popescu

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    D Vigil & C J Der

  3. Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    D R Lowy

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  1. X-Y Yang
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Correspondence to N C Popescu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Yang, XY., Guan, M., Vigil, D. et al. p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. Oncogene 28, 1401–1409 (2009). https://doi.org/10.1038/onc.2008.498

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