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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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COS Cells
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Chlorocebus aethiops
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Kinase 1 / metabolism
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Gene Expression Regulation
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Glioma / genetics
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Glioma / metabolism*
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Glioma / pathology
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Humans
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Ligands
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Molecular Sequence Data
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Phospholipase C gamma / genetics
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Phospholipase C gamma / metabolism
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Phosphorylation
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Shc Signaling Adaptor Proteins / genetics
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Shc Signaling Adaptor Proteins / metabolism*
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Signal Transduction / genetics*
Substances
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Ligands
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SHC4 protein, human
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Shc Signaling Adaptor Proteins
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ErbB Receptors
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Focal Adhesion Kinase 1
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PTK2 protein, human
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Phospholipase C gamma