The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor.
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 1γ, 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.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Brain Neoplasms, COS Cells, Cercopithecus aethiops, Extracellular Signal-Regulated MAP Kinases, Focal Adhesion Kinase 1, Gene Expression Regulation, Glioma, Humans, Ligands, Molecular Sequence Data, Phospholipase C gamma, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt, Receptor, Epidermal Growth Factor, Shc Signaling Adaptor Proteins, Signal Transduction
Amino Acid Sequence, Animals, Binding Sites, Brain Neoplasms, COS Cells, Cercopithecus aethiops, Extracellular Signal-Regulated MAP Kinases, Focal Adhesion Kinase 1, Gene Expression Regulation, Glioma, Humans, Ligands, Molecular Sequence Data, Phospholipase C gamma, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt, Receptor, Epidermal Growth Factor, Shc Signaling Adaptor Proteins, Signal Transduction
Mol. Biol. Cell
Date: Mar. 01, 2014
PubMed ID: 24430869
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