title: Cell fate decisions are specified by the dynamic ERK interactome.
abstract: Extracellular signal-regulated kinase (ERK) controls fundamental cellular functions, including cell fate decisions. In PC12, cells shifting ERK activation from transient to sustained induces neuronal differentiation. As ERK associates with both regulators and effectors, we hypothesized that the mechanisms underlying the switch could be revealed by assessing the dynamic changes in ERK-interacting proteins that specifically occur under differentiation conditions. Using quantitative proteomics, we identified 284 ERK-interacting proteins. Upon induction of differentiation, 60 proteins changed their binding to ERK, including many proteins that were not known to participate in differentiation. We functionally characterized a subset, showing that they regulate the pathway at several levels and by different mechanisms, including signal duration, ERK localization, feedback, crosstalk with the Akt pathway and differential interaction and phosphorylation of transcription factors. Integrating these data with a mathematical model confirmed that ERK dynamics and differentiation are regulated by distributed control mechanisms rather than by a single master switch.
authors: Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Alex
authors: A
authors: von Kriegsheim
authors: Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Daniela
authors: D
authors: Baiocchi
authors: Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Marc
authors: M
authors: Birtwistle
authors: Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: David
authors: D
authors: Sumpton
authors: Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Willy
authors: W
authors: Bienvenut
authors: MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors: Nicholas
authors: N
authors: Morrice
authors: Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors: Kayo
authors: K
authors: Yamada
authors: Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors: Angus
authors: A
authors: Lamond
authors: Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Gabriella
authors: G
authors: Kalna
authors: Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Richard
authors: R
authors: Orton
authors: Bioinformatics Research Centre, Department of Computing Science, University of Glasgow, Glasgow G12 8QQ, UK.
authors: David
authors: D
authors: Gilbert
authors: Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.|Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Walter
authors: W
authors: Kolch
mesh_terms: D000818:Animals; D019070:Cell Lineage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D016716:PC12 Cells; D011485:Protein Binding; D040901:Proteomics; D051381:Rats
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases