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

John M. Lambert, Que T. Lambert, Gary W. Reuther, Angeliki Malliri, David P. Siderovski, John Sondek, John G. Collard, Chaning J. Der

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228 Scopus citations

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.

Original languageEnglish
Pages (from-to)621-625
Number of pages5
JournalNature Cell Biology
Volume4
Issue number8
DOIs
StatePublished - Aug 2002

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    Lambert, J. M., Lambert, Q. T., Reuther, G. W., Malliri, A., Siderovski, D. P., Sondek, J., Collard, J. G., & Der, C. J. (2002). Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biology, 4(8), 621-625. https://doi.org/10.1038/ncb833