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How Vav proteins discriminate the GTPases Rac1 and RhoA from Cdc42

Oncogene volume 20, pages 8057–8065 (2001)Cite this article

Abstract

Vav proteins are GDP/GTP exchange factors for Rho/Rac GTPases that are activated by tyrosine phosphorylation. These proteins activate Rac1, RhoG, and RhoA but not the highly related Cdc42 protein. At present, there is no available information to explain this substrate selectivity at the structural level. Here we show that the selection of Vav proteins substrates is achieved at two different levels. On one hand, Vav proteins utilize some residues of the β2/β3 region of Rho/Rac GTPases (D49 and E54) to assure the specific binding to its substrate. In addition, these exchange factors need a second structural signal located in the β5 region of Rho/Rac proteins (residue K118) to promote proper GDP/GTP exchange. These results identify the amino acid residues that allow the discrimination of the Vav family substrates from Cdc42 and, in addition, demonstrate that the activation of specific Rho/Rac GTPases by these GEFs requires two concatenated events, binding and subsequent enzyme reaction, whose specificities are determined by two separate regions of Rho proteins.

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Acknowledgements

This work was supported by grants given to XR Bustelo by the National Cancer Institute (CA7373501), the Programa General del Conocimiento (PM99-0093; Spanish Ministry for Science and Technology), and the Programa FEDER (1FD97-2116; Spanish Ministry for Education). Work in Y Zheng's laboratory is supported by a grant from the National Institutes of Health (USA). XR Bustelo wishes to dedicate this article to his father, who has recently passed away.

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Author notes

  1. Nieves Movilla and Mercedes Dosil: N Movilla and M Dosil contributed equally to this work.

Authors and Affiliations

  1. Centro de Investigación del Cáncer, University of Salamanca-CSIC, 37007, Salamanca, Spain

    Nieves Movilla, Mercedes Dosil & Xosé R Bustelo

  2. Instituto de Biología Molecular y Celular del Cáncer, University of Salamanca-CSIC, 37007, Salamanca, Spain

    Nieves Movilla & Xosé R Bustelo

  3. Department of Biochemistry, University of Salamanca, 37007, Salamanca, Spain

    Mercedes Dosil

  4. Department of Molecular Sciences, University of Tennessee, Memphis, Tennessee, 38163, USA

    Yi Zheng

Authors
  1. Nieves Movilla
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  2. Mercedes Dosil
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  3. Yi Zheng
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  4. Xosé R Bustelo
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Correspondence to Xosé R Bustelo.

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Movilla, N., Dosil, M., Zheng, Y. et al. How Vav proteins discriminate the GTPases Rac1 and RhoA from Cdc42. Oncogene 20, 8057–8065 (2001). https://doi.org/10.1038/sj.onc.1205000

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