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Papers In Press, published online ahead of print April 12, 2004
Center for cardiovascular research, University of Rochester, Rochester, NY 14642
Corresponding Author: jun-ichi_abe{at}urmc.rochester.edu
Endothelial cell (EC) migration contributes to reendothelialization after angioplasty or rupture of atherosclerotic plaques. ERK1/2 translocates to the nucleus and activates transcription factors such as Elk1 and Egr-1 during reendothelialization. Since ERK1/2 does not possess a nuclear localization signal (NLS), its mechanism of translocation and accumulation in the nucleus remains unclear. Since Gab1 has a putative NLS in its N-terminal region, and Gab1 associates with phosphorylated ERK1/2, we hypothesized that Gab1 participates in ERK1/2 and Egr-1 nuclear accumulation. Using regenerating EC as a model system, we found that endogenous Gab1 translocates into the nucleus in migrating EC. Wild type RFP-tagged Gab1 could be observed in both nucleus and cytoplasm, while the putative NLS deletion mutant (NLS-Gab1) specifically localized in the cytoplasm. In addition, reduction of Gab1 expression by antisense Gab1 oligoes or overexpression of NLS-Gab1 inhibited serum-induced ERK1/2 and Egr-1 nuclear accumulation, suggesting a functional role for the NLS of Gab1 and a role for Gab1 and ERK1/2 interaction in ERK1/2-Egr-1 nuclear accumulation. To investigate whether Gab1 and ERK1/2 interaction is critical for ERK1/2 and Egr-1 nuclear accumulation, we created a dominant negative Gab1 construct that consisted of the c-Met binding domain (aa 442-536) of Gab1 (Gab1-MBD). We found that overexpression of Gab1-MBD disrupted serum-induced Gab1/ERK1 interaction and inhibited ERK1 and Egr-1 nuclear accumulation. These data suggest that Gab1-ERK1/2 binding and their nuclear translocation play a crucial role in Egr-1 nuclear accumulation.
J. Biol. Chem, 10.1074/jbc.M309371200
Submitted on August 25, 2003
Revised on April 12, 2004
Accepted on April 12, 2004
ERK1/2 associates with the c-Met binding domain of Gab1: Role in ERK1/2 and Egr-1 nuclear accumulation
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