Abstract
The small guanine nucleotide (GTP)-binding protein Rac regulates mitogen-induced cytoskeletal changes and c-Jun amino-terminal kinase (JNK), and its activity is required for Ras-mediated cell transformation1. Epistatic analysis placed Rac as a key downstream target in Ras signalling2; however, the biochemical mechanism regulating the cross-talk among these small GTP-binding proteins remains to be elucidated. Eps8 (relative molecular mass 97,000) is a substrate of receptors with tyrosine kinase activity3 which binds, through its SH3 domain, to a protein designated E3b1/Abi-1 (refs 4, 5). Here we show that Eps8 and E3b1/Abi-1 participate in the transduction of signals from Ras to Rac, by regulating Rac-specific guanine nucleotide exchange factor (GEF) activities. We also show that Eps8, E3b1 and Sos-1 form a tri-complex in vivo that exhibits Rac-specific GEF activity in vitro. We propose a model in which Eps8 mediates the transfer of signals between Ras and Rac, by forming a complex with E3b1 and Sos-1.
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Acknowledgements
We thank J. Downward, E. Van Obberghen-Shilling, S. Meloche, L. B. Areces, A. Mongiovi and L. Lanfrancone for the gift of various plasmids and mutants; E. Frittoli and S. Beckman for technical assistance; and E. Migliaccio and all the members of the Di Fiore and Betsholtz laboratories for discussions. The microinjector Axiovert 100 (Zeiss) was donated by the Lattanzio family.
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Scita, G., Nordstrom, J., Carbone, R. et al. EPS8 and E3B1 transduce signals from Ras to Rac. Nature 401, 290–293 (1999). https://doi.org/10.1038/45822
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DOI: https://doi.org/10.1038/45822
