Journal
EXPERIMENTAL CELL RESEARCH
Volume 316, Issue 19, Pages 3239-3253Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2010.09.001
Keywords
EGER; Src; Recycling endosome; Plasma membrane signalling
Categories
Funding
- UCL
- F.R.S./FNRS
- Televie
- Region bruxelloise
- Region wallonne
- Loterie Nationale
- Actions de recherche concertees
- Interuniversity Attraction poles
- EU (EUNEPHRON)
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Src, a non-receptor tyrosine kinase, is a key signal transduction partner of epidermal growth factor (EGF) receptor (EGFR). In human breast cancer, EGFR and Src are frequently over-expressed and/or over-activated. Although reciprocal activation is documented, mechanisms underlying Src: EGFR interactions are incompletely understood. We here exploited ts/v-Src thermo-activation in MDCK monolayers to test whether acute Src activation impacts on signalling and trafficking of non-liganded EGFR. We found that thermo-activation caused rapid Src recruitment to the plasma membrane, concomitant association with EGFR, and its phosphorylation at Y845 and Y1173 predominantly at the cell surface. Like low EGF concentrations, activated Src (i) decreased EGF surface binding without affecting the total EGFR pool; (ii) triggered EGER endocytosis via clathrin-coated vesicles; (iii) and led to its sequestration in perinuclear/recycling endosomes with avoidance of multivesicular bodies and lysosomal degradation. Combined Src activation and EGF were synergistic for EGFR-Y845 and -Y1173 phosphorylation at some endosomes. We conclude that acute effects of Src in MDCK cells may mimic those of low EGF on EGFR activation and redistribution. Src:EGFR interactions may be sufficient to trigger EGFR activation and might contribute to its local signalling, without requiring either soluble extracellular signal or receptor over-expression. (C) 2010 Elsevier Inc. All rights reserved.
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