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Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism

Nature Cell Biology volume 4, pages 621–625 (2002)Cite this article

Abstract

Rac is a member of the Ras superfamily of GTPases and functions as a GDP/GTP-regulated switch1. Formation of active Rac-GTP is stimulated by Dbl family guanine nucleotide exchange factors (GEFs), such as Tiam1 (ref. 2). Once activated, Rac stimulates signalling pathways that regulate actin organization, gene expression and cellular proliferation. Rac also functions downstream of the Ras oncoprotein in pathways that stimulate membrane ruffling3, growth transformation4,5, activation of the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase6, activation of the NF-κB transcription factor and promotion of cell survival7,8. Although recent studies support phosphatidylinositol 3-OH kinase (PI(3)K)-dependent mechanisms through which Ras might activate Rac (refs 9,10), the precise mechanism remains to be determined. Here we demonstrate that Tiam1, a Rac-specific GEF, preferentially associates with activated GTP-bound Ras through a Ras-binding domain. Furthermore, activated Ras and Tiam1 cooperate to cause synergistic formation of Rac-GTP in a PI(3)K-independent manner. Thus, Tiam1 can function as an effector that directly mediates Ras activation of Rac.

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Figure 1: Ras activates Rac and interacts with Tiam1.
Figure 2: Tiam1-RBD is necessary and sufficient for the association of Ras with Tiam1.
Figure 3: Tiam1 and Ras cooperate to activate Rac.
Figure 4: Ras-mediated activation of Rac is impaired in Tiam1-deficient fibroblasts.

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Acknowledgements

We thank C.I. Behe and M. Pham for technical assistance, and M. Rand for assistance in figure and manuscript preparation. We thank M. Ostrowski, G. Bollag, J. Downward, C. Hauser and B. Mayer for plasmid constructs. This work was supported by grants from the National Institutes of Health to D.P.S. (GM62338), J.S.(GM62299), and C.J.D. (CA69577), as well as a career award from the Pew Charitable Trusts (J.S.). G.W.R. is a Leukemia and Lymphoma Society Special Fellow. D.P.S. is a Year 2000 Scholar of the EJLB Foundation and a recipient of the Burroughs-Wellcome New Investigator Award in the Basic Pharmacological Sciences. Part of this work was supported by the Dutch Cancer Society, the European Community and the Association for International Cancer Research (J.G.C.).

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Authors and Affiliations

  1. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    John M. Lambert, Que T. Lambert, Gary W. Reuther, David P. Siderovski, John Sondek & Channing J. Der

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    John M. Lambert, Que T. Lambert, Gary W. Reuther, David P. Siderovski, John Sondek & Channing J. Der

  3. Division of Cell Biology, The Netherlands Cancer Institute, Plesmaniaan 121, Amsterdam, 1066, CX, The Netherlands

    Angeliki Malliri & John G. Collard

  4. UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    David P. Siderovski

  5. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    John Sondek

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Correspondence to Channing J. Der.

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Lambert, J., Lambert, Q., Reuther, G. et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol 4, 621–625 (2002). https://doi.org/10.1038/ncb833

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