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A more recent version of this article appeared on January 1, 2004
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Submitted on June 21, 2003
Revised on September 4, 2003
Accepted on September 4, 2003
1 The FIRC Institute for Molecular Oncology, Via Adamello 16, 20134, Milan, Italy, Department of Experimental Oncology, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy
2 Department of Experimental Oncology, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy
3 The FIRC Institute for Molecular Oncology, Via Adamello 16, 20134, Milan, Italy
4 The FIRC Institute for Molecular Oncology, Via Adamello 16, 20134, Milan, Italy, University of Milan, Medical School, 20122, Milan, Italy, Department of Experimental Oncology, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy
* Corresponding author.
Sos-1, a guanine nucleotide exchange factor (GEF), eps8 and Abi1,
two signaling proteins, and the lipid kinase Phosphoinositide 3-kinase
(PI3-K), assemble in a multimolecular complex required for Rac
activation leading to actin cytoskeletal remodeling. Consistently,
eps8 -/- fibroblasts fail to form membrane ruffles in
response to growth factor stimulation. Surprisingly,
eps8 null mice are healthy, fertile and display no overt
phenotype, suggesting the existence of functional redundancy within
this pathway. Here, we describe the identification and characterization
of a family of eps8-related proteins, comprising three novel gene
products, named eps8L1, eps8L2, and eps8L3. Eps8Ls display collinear
topology and 27-42% identity to eps8. Similarly to eps8, eps8Ls
interact with Abi1 and Sos-1; however, only eps8L1 and eps8L2 activate
the Rac-GEF activity of Sos-1, and bind to actin in vivo. Consistently,
eps8L1 and eps8L2, but not eps8L3, localize to PDGF-induced,
F-actin-rich ruffles, and restore receptor tyrosine kinase
(RTK)-mediated actin remodeling when expressed in eps8
-/- fibroblasts. Thus, the eps8Ls define a novel family of proteins
responsible for functional redundancy in the RTK-activated signaling
pathway leading to actin remodeling. Finally, the patterns of
expression of eps8 and eps8L2 in mice are
remarkably overlapping, thus providing a likely explanation for the
lack of overt phenotype in eps8 null mice.
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