title: EPS8 and E3B1 transduce signals from Ras to Rac.
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 transformation. Epistatic analysis placed Rac as a key downstream target in Ras signalling; 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 which binds, through its SH3 domain, to a protein designated E3b1/Abi-1. 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Scita
authors.forename: J
authors.initials: J
authors.lastname: Nordstrom
authors.forename: R
authors.initials: R
authors.lastname: Carbone
authors.forename: P
authors.initials: P
authors.lastname: Tenca
authors.forename: G
authors.initials: G
authors.lastname: Giardina
authors.forename: S
authors.initials: S
authors.lastname: Gutkind
authors.forename: M
authors.initials: M
authors.lastname: Bjarnegård
authors.forename: C
authors.initials: C
authors.lastname: Betsholtz
authors.forename: P P
authors.initials: PP
authors.lastname: Di Fiore
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005822:Genetic Vectors; D020662:Guanine Nucleotide Exchange Factors; D006160:Guanosine Triphosphate / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C513733:ABI1 protein, human; C513734:Abi1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C489989:EPS8 protein, human; C083430:Eps8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D018631:ras Proteins