Cell fate decisions are specified by the dynamic ERK interactome

Signalling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Nature Cell Biology (Impact Factor: 19.68). 12/2009; 11(12):1458-64. DOI: 10.1038/ncb1994
Source: PubMed


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.

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Available from: Alexander Von Kriegsheim
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    • "Both amplitude (dose) and duration of input signals provide information that regulates cellular decisions. The duration of Epidermal Growth Factor (EGF) stimulation modulates ERK dynamics and controls differentiation (Santos et al., 2007; von Kriegsheim et al., 2009; Ahmed et al., 2014). Glucose sensing in plants showed that cells have gene regulatory network mechanisms to allow similar responses to a short, intense or sustained, moderate stimulus (Fu et al., 2014). "
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    • "Neurite outgrowth is an important aspect of neuronal plasticity and regeneration in neuropathological conditions and neural injury [27]. Consistent with previous reports [28,29], in this study, more than 20% of NGF-stimulated PC12 cells had neurites that were twice the cell body length after exposure to RA4. Although the effects of IH on neuronal cell differentiation remain poorly understood, a previous study reported that 10 cycles of IH (1% O2 for 24 h, following a 24-h recovery period under RA) suppressed retinoic acid-induced differentiation of neuroblastoma cells [9]. "
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