ERK-MAP kinase signalling: biological context, cellular location, signal strength and duration dictate cell fate


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John Blenis

Harvard Medical School, Boston, USA

Abstract

ERK-MAP kinase signalling: biological context, cellular location, signal strength and duration dictate cell fate

The Ras/ERK-MAP kinase pathway has been extensively studied and is active under a variety of cellular conditions. Factors such as cell-surface receptor density, expression of scaffolding proteins, the surrounding extracellular matrix, and the interplay between kinases and phosphatases modulate the strength, duration and location of ERK signalling. These differences in ERK signalling as well as cellular context have been linked to distinct cell fates. How cells can sense subtle differences in the spatial and temporal regulation of ERK signalling to differentially promote cell proliferation, migration, survival and/or tumourigenesis have more recently received much attention. We have described a process whereby the Ras effectors, ERK and the ERK-regulated kinase, RSK, not only contribute to the induction of certain immediate-early genes (IEGs), but depending on the spatial distribution and temporal qualities of ERK, can markedly alter the qualitative and quantitative features of the expression of IEG-encoded protein products and downstream responses. As a result, IEG products provide a molecular interpretation of ERK dynamics, enabling the cell to program an appropriate biological response. ERK “sees” its targets through specific domain interactions. The ability of ERK to selectively interact with its DEF-domain containing substrates contributes to the ERK/IEG sensing mechanism. In addition to the importance of this interaction in fibroblast proliferation, we now provide evidence for the role of this interaction in regulating the epithelial-to-mesenchymal transformation of breast epithelial MCF10a cells in response to Ras/ERK-MAPK signalling.