Cell fate decisions are specified by the dynamic ERK interactome.
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.
von Kriegsheim
Alex
A
Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Baiocchi
Daniela
D
Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Birtwistle
Marc
M
Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Sumpton
David
D
Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Bienvenut
Willy
W
Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Morrice
Nicholas
N
MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Yamada
Kayo
K
Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Lamond
Angus
A
Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Kalna
Gabriella
G
Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Orton
Richard
R
Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, Glasgow G12 8QQ, UK.
Gilbert
David
D
Bioinformatics Research Centre, Department of Computing Science, University of Glasgow, Glasgow G12 8QQ, UK.
Kolch
Walter
W
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.
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
D048049:Extracellular Signal-Regulated MAP Kinases