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Molecular interpretation of ERK signal duration by immediate early gene products

Nature Cell Biology volume 4, pages 556–564 (2002)Cite this article

Abstract

The duration of intracellular signalling is associated with distinct biological responses, but how cells interpret differences in signal duration are unknown. We show that the immediate early gene product c-Fos functions as a sensor for ERK1 (extracellular-signal-regulated kinase 1) and ERK2 signal duration. When ERK activation is transient, its activity declines before the c-Fos protein accumulates, and under these conditions c-Fos is unstable. However, when ERK signalling is sustained, c-Fos is phosphorylated by still-active ERK and RSK (90K-ribosomal S6 kinase). Carboxy-terminal phosphorylation stabilizes c-Fos and primes additional phosphorylation by exposing a docking site for ERK, termed the FXFP (DEF) domain. Mutating the DEF domain disrupts the c-Fos sensor and c-Fos-mediated signalling. Other immediate early gene products that control cell cycle progression, neuronal differentiation and circadium rhythms also contain putative DEF domains, indicating that multiple sensors exist for sustained ERK signalling. Together, our data identify a general mechanism by which cells can interpret differences in ERK activation kinetics.

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Figure 1: Differential responsiveness of Swiss 3T3 fibroblasts to growth factors.
Figure 2: ERK and RSK prime c-Fos for additional regulation by mitogens.
Figure 3: An ERK-docking DEF domain mediates phosphorylation of primed c-Fos.
Figure 4: ERK phosphorylates Thr 325 and Thr 331 in primed c-Fos.
Figure 5: Characterization of the phospho-Thr 325-specific antiserum.
Figure 6: c-Fos is a sensor for ERK signal duration in vivo.
Figure 7: ERK-docking to c-Fos is required for Fos-mediated signalling.
Figure 8: Molecular interpretation of ERK signal duration.

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Acknowledgements

We thank T. Curran, J.-D. Lee, M. Cobb and M. McMahon for reagents. We also thank J. Brugge, T. Rapoport and members of the Blenis laboratory for critical reading of this manuscript, and J. Brugge, L. Cantley, B. Neel, and A. Kazlauskas for many helpful discussions. This work was supported by National Institutes of Health grant RO1CA46595 (J.B.), a Special Grant for Research from the American Cancer Society, New England Division (L.O.M.) and NIH grants F32-CA68712 (S.S.) and F32-CA69808 (D.C.F.).

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  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, MA, USA

    Leon O. Murphy, Sallie Smith, Rey-Huei Chen, Diane C. Fingar & John Blenis

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Figure S1. Nuclear accumulation of active ERK1/2 and c-Fos in growth factor- treated Swiss 3T3 cells. addition of cycloheximide (+) or vehicle (-). (PDF 1322 kb)

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Murphy, L., Smith, S., Chen, RH. et al. Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol 4, 556–564 (2002). https://doi.org/10.1038/ncb822

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