Temporal regulation of EGF signalling networks by the scaffold protein Shc1

Yong Zheng, Cunjie Zhang, David R. Croucher, Mohamed A. Soliman, Nicole St-Denis, Adrian Pasculescu, Lorne Taylor, Stephen A. Tate, W. Rod Hardy, Karen Colwill, Anna Yue Dai, Rick Bagshaw, James W. Dennis, Anne-Claude Gingras, Roger J. Daly and Tony Pawson ()
Additional contact information
Yong Zheng: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Cunjie Zhang: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
David R. Croucher: Systems Biology Ireland, Conway Institute, University College Dublin, Dublin 4, Ireland
Mohamed A. Soliman: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Nicole St-Denis: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Adrian Pasculescu: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Lorne Taylor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Stephen A. Tate: AB SCIEX, Concord, Ontario L4K 4V8, Canada
W. Rod Hardy: University of Massachusetts Medical School
Karen Colwill: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Anna Yue Dai: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Rick Bagshaw: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
James W. Dennis: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Anne-Claude Gingras: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
Roger J. Daly: School of Biomedical Sciences, Monash University, Victoria 3800, Australia
Tony Pawson: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada

Nature, 2013, vol. 499, issue 7457, 166-171

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12308

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