title: Temporal regulation of EGF signalling networks by the scaffold protein Shc1.
abstract: Cell-surface receptors frequently use scaffold proteins to recruit cytoplasmic targets, but the rationale for this is uncertain. Activated receptor tyrosine kinases, for example, engage scaffolds such as Shc1 that contain phosphotyrosine (pTyr)-binding (PTB) domains. Using quantitative mass spectrometry, here we show that mammalian Shc1 responds to epidermal growth factor (EGF) stimulation through multiple waves of distinct phosphorylation events and protein interactions. After stimulation, Shc1 rapidly binds a group of proteins that activate pro-mitogenic or survival pathways dependent on recruitment of the Grb2 adaptor to Shc1 pTyr sites. Akt-mediated feedback phosphorylation of Shc1 Ser 29 then recruits the Ptpn12 tyrosine phosphatase. This is followed by a sub-network of proteins involved in cytoskeletal reorganization, trafficking and signal termination that binds Shc1 with delayed kinetics, largely through the SgK269 pseudokinase/adaptor protein. Ptpn12 acts as a switch to convert Shc1 from pTyr/Grb2-based signalling to SgK269-mediated pathways that regulate cell invasion and morphogenesis. The Shc1 scaffold therefore directs the temporal flow of signalling information after EGF stimulation.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Cunjie
authors.initials: C
authors.lastname: Zhang
authors.forename: David R
authors.initials: DR
authors.lastname: Croucher
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Soliman
authors.forename: Nicole
authors.initials: N
authors.lastname: St-Denis
authors.forename: Adrian
authors.initials: A
authors.lastname: Pasculescu
authors.forename: Lorne
authors.initials: L
authors.lastname: Taylor
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Tate
authors.forename: W Rod
authors.initials: WR
authors.lastname: Hardy
authors.forename: Karen
authors.initials: K
authors.lastname: Colwill
authors.forename: Anna Yue
authors.initials: AY
authors.lastname: Dai
authors.forename: Rick
authors.initials: R
authors.lastname: Bagshaw
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
mesh_terms: D000818:Animals; D001940:Breast / Q000166:cytology; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D051380:GRB2 Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013997:Time Factors
chemical_list: D051380:GRB2 Adaptor Protein; D046912:Multiprotein Complexes; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C573947:PEAK1 protein, human; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases