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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Temporal regulation of EGF signalling networks by the scaffold protein Shc1
Nature, Volume 499, No. 7457, Year 2013
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Description
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. © 2013 Macmillan Publishers Limited. All rights reserved.
Authors & Co-Authors
Zheng, Yong
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Zhang, Cunjie
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Croucher, David R.
Ireland, Dublin
University College Dublin
Soliman, M. A.
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Canada, Toronto
University of Toronto
Egypt, Cairo
Faculty of Pharmacy
St-Denis, Nicole A.
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Pasculescu, Adrian
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Taylor, Lorne
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Tate, Stephen A.
United States, Framingham
Sciex
Rod Hardy, W.
United States, Worcester
University of Massachusetts Chan Medical School
Colwill, Karen
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Dai, Anna Yue
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Bagshaw, Richard D.
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Dennis, James W.
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Canada, Toronto
University of Toronto
Gingras, Anne Claude
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Canada, Toronto
University of Toronto
Daly, Roger J.
Australia, Clayton
Monash University
Australia, Sydney
Garvan Institute of Medical Research
Pawson, Tony J.
Canada, Toronto
The Lunenfeld-tanenbaum Research Institute of University of Toronto
Canada, Toronto
University of Toronto
Statistics
Citations: 262
Authors: 16
Affiliations: 8
Identifiers
Doi:
10.1038/nature12308
ISSN:
00280836
e-ISSN:
14764687
Study Approach
Quantitative