Tyrosine-phosphorylated Hic-5 inhibits epidermal growth factor-induced lamellipodia formation |
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Authors: | Hetey Sara E Lalonde David P Turner Christopher E |
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Affiliation: | Department of Cell and Developmental Biology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA. |
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Abstract: | The focal adhesion protein Hic-5, a homologue to paxillin, has been shown to be tyrosine-phosphorylated in fibroblasts in response to stimuli such as osmotic stress, serum, LPA and endothelin. However, the function of this modification to Hic-5 is unclear. Herein, we show that Hic-5 is tyrosine-phosphorylated on residues 38 and 60 following epidermal growth factor (EGF) treatment of COS-7 cells, coincident with an increase in peripheral actin reorganization. To explore the role of Hic-5 phosphorylation in this process, we introduced wild-type (WT) and mutant Hic-5 constructs into COS-7 cells and determined that EGF-induced lamellipodia formation was suppressed by WT Hic-5. This effect required localization to focal adhesions as well as phosphorylation of Hic-5 as overexpression of both a non-targeting and a non-phosphorylatable Hic-5 failed to inhibit peripheral actin reorganization. Interestingly, overexpression of non-phosphorylatable Y31/118F or WT paxillin did not affect lamellipodia formation, indicating that this effect is specific to Hic-5. The EGF-induced lamellipodia were Rac-dependent and overexpressed WT Hic-5, but not non-phosphorylatable Hic-5 inhibited Rac activation. Our data suggest that Hic-5 tyrosine phosphorylation functions to regulate signaling associated with lamellipodia formation, a process fundamental to cell motility. |
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Keywords: | Hic-5, hydrogen peroxide-inducible clone-5 EGF, epidermal growth factor PDGF, platelet-derived growth factor ARA55, androgen receptor associated protein 55 ECM, extracellular matrix EMT, epithelial-mesenchymal transition PBS2, paxillin binding subdomain 2 PBD, p21 binding domain Csk, carboxyl-terminal Src kinase Pv, pervanadate |
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