Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 25, Issue 6, Pages 739-752Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E13-08-0434
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Funding
- Natural Sciences and Engineering Research Council of Canada [RG327372]
- Brain Tumour Foundation of Canada
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada University Faculty Award
- Canadian Institutes of Health Research Vanier Canada Graduate Scholarship
- University of Guelph Brock Doctoral Scholarship
- Tier Two Canada Research Chair
- Ontario Genomics Institute Summer Fellowship
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Proto-oncogenic Src homology and collagen (Shc) proteins have been considered archetypal adaptors of epidermal growth factor receptor (EGFR)-mediated signaling. We report that in addition to its role as an EGFR-binding partner and Grb2 platform, ShcD acts noncanonically to promote phosphorylation of select EGFR residues. Unexpectedly, Y1068, Y1148, and Y1173 are subject to ShcD-induced, cell-autonomous hyperphosphorylation in the absence of external stimuli. This response is not elicited by other Shc proteins and requires the intrinsic EGFR kinase, as well as the ShcD phosphotyrosine-binding (PTB) domain. Assessments of Erk, Akt, phospholipase C 1 gamma, and FAK pathways reveal no apparent distal signaling targets of ShcD. Nevertheless, the capacity of cultured cells to repopulate a wounded monolayer is markedly accelerated by ShcD in an EGFR kinase-dependent manner. Furthermore, detection of overexpressed ShcD coincident with EGFR phosphorylation in human gliomas suggests a clinical application for these findings. We thus demonstrate unique and relevant synergy between ShcD and EGFR that is unprecedented among signaling adaptors.
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