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The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor.


ABSTRACT: 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?, 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.

SUBMITTER: Wills MK 

PROVIDER: S-EPMC3952845 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor.

Wills Melanie K B MK   Tong Jiefei J   Tremblay Sylvie L SL   Moran Michael F MF   Jones Nina N  

Molecular biology of the cell 20140115 6


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 othe  ...[more]

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