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Signal transduction

What goes up must come down

Nature volume 394, pages 23–24 (1998)Cite this article

Eukaryotic cells can adjust their metabolism, growth and differentiation in response to hormones, growth factors, neurotransmitters and stress by reversible protein phosphorylation — the addition and removal of phosphate groups. To ensure the efficacy of intracellular signals conveyed in this manner, opposing protein kinase and protein phosphatase enzymes (which add and remove phosphate groups, respectively) have evolved a high degree of substrate specificity, and systems for precise intracellular targeting1,2. Reports by Westphal et al.3 and Camps et al.4 in Science now highlight an additional molecular device for the feedback regulation of kinase signalling pathways. Here, a protein kinase, which is itself regulated by protein phosphorylation, becomes the substrate of a specific protein phosphatase in a self-moderating signalling complex.

Westphal et al.3 describe an interaction between the Ca2+-calmodulin-dependent protein kinase IV (CaMKIV) and the ubiquitous and evolutionarily conserved protein phosphatase 2A (PP2A). CaMKIV is activated in a Ca2+-dependent manner involving phosphorylation by the upstream kinase Ca2+-calmodulin-dependent protein kinase kinase (CaMKK). Activation is transient and reversible, even in the presence of high levels of intracellular Ca2+. The authors found that PP2A binds to the region of CaMKIV that encompasses the kinase catalytic domain, but that this binding is independent of CaMKK-mediated phosphorylation. Moreover, although CaMKK-driven activation of CaMKIV is reversed by PP2A, the enzymatic activity of neither CaMKIV nor PP2A is required for their physical interaction, revealing a stable interaction.

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Figure 1: Signalling cascade responding to ‘on’ and ‘off’ signals.

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  1. the Friedrich Miescher Institute, PO Box 2543, 4002, Basel, Switzerland

    David R. H. Evans & Brian A. Hemmings

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  1. David R. H. Evans
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Evans, D., Hemmings, B. What goes up must come down. Nature 394, 23–24 (1998). https://doi.org/10.1038/27782

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