Phosphorylation: The key to staying faithful

Abstract

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 2 | MARCH 2001 | 167 The cascades in which mitogen-activated protein kinases (MAPKs) play a part can have radically different outcomes, making promiscuity among MAPKs dangerous to the cell.Yet each pathway comprises closely related components. How do MAPKs remain faithful to their pathways? In the 1 February issue of EMBO Journal, Takuji Tanoue and colleagues explain one mechanism. Remarkably, this relies on the identity of just two amino acids. We know of three types of MAPKs, each with their own cascade. The extracellular-signal regulated kinases (ERKs) are activated by growth factors, generally leading to proliferation, whereas p38s and Jun-Nterminal kinases (JNKs) are activated by stress signals, usually causing cellcycle arrest or apoptosis. Each MAPK has to interact with the kinases that activate it (MAPKKs), the phosphatases that inactivate it (MKPs) and its substrates, which are also kinases (MAPKAPKs). A single acidic site outside the active site — the common docking or CD site — interacts with all these molecules, but it doesn’t explain the different binding specificities of the MAPKs. Could there be another site that regulates specificity? Mutation of the CD in p38 reduced, but didn’t completely prevent, binding of the p38-specific MAPKAPK 3pk, implying that another docking site exists. By searching for charged residues and systematically mutating them, the authors identified a pair of residues on p38, Glu 160 and Asp 161, that account for this residual binding. Mutation of the CD site and this second site, which they dubbed the ED site, markedly reduced the ability of p38 to phosphorylate 3pk. The corresponding residues in ERK2 are two threonine residues. Mutation of these to Glu and Asp enabled ERK2 to bind 3pk, and mutation of ERK2’s CD site to make it identical to p38’s improved the interaction further. Extending these studies to other MAPKAPKs and MKPs revealed that, although the CD is necessary for binding, the nature of the ED regulates specificity. Together, the two sites form a groove with two pins in it. Only if it can interact with both pins can a MAPKinteracting protein do its business. Cath Brooksbank References and links ORIGINAL RESEARCH PAPER Tanoue, T. et al. Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions. EMBO J. 20, 466–479 (2001) FURTHER READING Tanoue, T. et al. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nature Cell Biol. 2, 110–116 (2000) WEB SITE Mammalian MAPK signalling pathways IN BRIEF

DOI: 10.1038/35056503

Cite this paper

@article{Brooksbank2001PhosphorylationTK, title={Phosphorylation: The key to staying faithful}, author={Cath Brooksbank}, journal={Nature Reviews Molecular Cell Biology}, year={2001}, volume={2}, pages={167-167} }