Temporal regulation of EGF signalling networks by the scaffold protein Shc1

Yong Zheng, Cunjie Zhang, David 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 John Daly, Tony Pawson

Research output: Contribution to journalArticleResearchpeer-review

165 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)166 - 171
Number of pages6
JournalNature
Volume499
Issue number7457
DOIs
Publication statusPublished - 2013

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