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Extracellular signal-regulated kinase (ERK) controls fundamental cellular functions, including cell fate decisions(1,2). In PC12, cells shifting ERK activation from transient to sustained induces neuronal differentiation(3). As ERK associates with both regulators and effectors(4), 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.
- SIGNAL-REGULATED KINASE
- FACIO-CUTANEOUS SYNDROME
- NERVE GROWTH-FACTOR
- MAP KINASE
FingerprintDive into the research topics of 'Cell fate decisions are specified by the dynamic ERK interactome'. Together they form a unique fingerprint.
- 2 Finished
- 215 Citations
- 1 Article
von Kriegsheim, A., Baiocchi, D., Birtwistle, M., Sumpton, D., Bienvenut, W., Morrice, N., Yamada, K., Lamond, A., Kalna, G., Orton, R., Gilbert, D. & Kolch, W., 18 Feb 2022, (E-pub ahead of print) In: Nature Cell Biology. 24, p. 400 1 p.
Research output: Contribution to journal › Article › peer-reviewOpen Access