EPS8 and E3B1 transduce signals from Ras to Rac.
Scita, Giorgio *+; Nordstrom, Johan +++; Carbone, Roberta *; Tenca, Pierluigi *; Giardina, Giuseppina *; Gutkind, Silvio [S]; Bjarnegard, Mattias ++; Betshoitz, Christer ++; Di Fiore, Pier Paolo *[//]
[Letter] Nature. 401(6750):290-293, September 16, 1999.

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The small guanine nucleotide (GTP)-binding protein Rac regulates mitogen-induced cytoskeletal changes and c-Jun aminoterminal kinase (JNK), and its activity is required for Ras-mediated cell transformation 1. Epistatic analysis placed Rac as a key downstream target in Ras signalling 2; 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 activity 3 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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