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Cell fate decisions are specified by the dynamic ERK interactome

Nature Cell Biology volume 11, pages 1458–1464 (2009)Cite this article

An Author Correction to this article was published on 18 February 2022

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Abstract

Extracellular signal-regulated kinase (ERK) controls fundamental cellular functions, including cell fate decisions1,2. In PC12, cells shifting ERK activation from transient to sustained induces neuronal differentiation3. As ERK associates with both regulators and effectors4, 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.

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Figure 1: Identification of dynamic ERK1 interactions.
Figure 2: NF1 controls Ras activity and signal duration.
Figure 3: Regulation of ERK localization in PC12 cells by PEA-15.
Figure 4: Differential regulation of transcriptional repressors by EGF and NGF in PC12 cells.
Figure 5: Kinetic mathematical model of the ERK pathway in PC12 cells.

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Acknowledgements

We thank P. Mortensen for help with MSQuant, A. Pitt and C. Ward for help with MS, O.Rath for the design of primers and G. Cesareni and A. Chatraryamontri for help with submission of the interaction data to the IMEx consortium through MINT. The work was supported by the European Union Interaction Proteome project (LSHG-CT-2003-505520), the RASOR project (BBSRC and EPSRC) and Cancer Research UK.

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Author notes

  1. Daniela Baiocchi

    Present address: Current address: Experimental Pathology, University of Bologna, 40126 Bologna, Italy.,

  2. David Gilbert

    Present address: Current address: School of Information Systems, Computing & Mathematics, Brunel University, Uxbridge, Middlesex, UB8 3PH, UK.,

  3. Marc Birtwistle & Walter Kolch

    Present address: Current address: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.,

  4. Daniela Baiocchi and Marc Birtwistle: These authors contributed equally to this work.

Authors and Affiliations

  1. Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, G61 1BD, Glasgow, UK

    Alex von Kriegsheim, Daniela Baiocchi, Marc Birtwistle, David Sumpton, Willy Bienvenut, Gabriella Kalna & Walter Kolch

  2. MRC Protein Phosphorylation Unit, University of Dundee, Scotland, DD1 5EH, Dundee, UK

    Nicholas Morrice

  3. Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Scotland, DD1 5EH, Dundee, UK

    Kayo Yamada & Angus Lamond

  4. Department of Computing Science, Bioinformatics Research Centre, University of Glasgow, G12 8QQ, Glasgow, UK

    David Gilbert

  5. Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, G12 8QQ, Glasgow, UK

    Richard Orton & Walter Kolch

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Contributions

A.v.K. performed most of the experiments, analysed the data and wrote the paper; D.B. performed the PEA-15 experiments; M.B., R.O. and D.G. generated the mathematical model; D.S., W.B., A.v.K., N.M., K.Y., and A.L. generated and analysed MS data; G.K. performed bioinformatic analysis; W.K. conceived the study and edited the paper.

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Correspondence to Walter Kolch.

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The authors declare no competing financial interests.

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von Kriegsheim, A., Baiocchi, D., Birtwistle, M. et al. Cell fate decisions are specified by the dynamic ERK interactome. Nat Cell Biol 11, 1458–1464 (2009). https://doi.org/10.1038/ncb1994

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