title: 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 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.
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Department of Molecular Genetics and Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
authors.forename: Melanie K B
authors.initials: MK
authors.lastname: Wills
authors.forename: Jiefei
authors.initials: J
authors.lastname: Tong
authors.forename: Sylvie L
authors.initials: SL
authors.lastname: Tremblay
authors.forename: Michael F
authors.initials: MF
authors.lastname: Moran
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D008024:Ligands; C519335:SHC4 protein, human; D055765:Shc Signaling Adaptor Proteins; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma