Dual‐specificity MAP kinase phosphatases (MKPs)

Christopher J Caunt,Stephen M Keyse

doi:10.1111/j.1742-4658.2012.08716.x

Christopher J Caunt, Stephen M Keyse

Open Access

https://doi.org/10.1111/j.1742-4658.2012.08716.x

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Journal: FEBS Journal	Publication Date: Aug 28, 2012
Citations: 447	License type: unspecified-oa

Affiliation: University of Bath, Ninewells Hospital

Abstract

Dual-specificity MAP kinase phosphatases (MKPs) provide a complex negative regulatory network that acts to shape the duration, magnitude and spatiotemporal profile of MAP kinase activities in response to both physiological and pathological stimuli. Individual MKPs may exhibit either exquisite specificity towards a single mitogen-activated protein kinase (MAPK) isoform or be able to regulate multiple MAPK pathways in a single cell or tissue. They can act as negative feedback regulators of MAPK activity, but can also provide mechanisms of crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules. In this review, we explore the current state of knowledge with respect to the regulation of MKP expression levels and activities, the mechanisms by which individual MKPs recognize and interact with different MAPK isoforms and their role in the spatiotemporal regulation of MAPK signalling.

Highlights

Mitogen-activated protein kinases (MAPKs) are components of highly conserved signal transduction pathways, which act in a concerted manner to determine both physiological and pathological responses to a wide variety of extracellular and intracellular stimuli [1,2]
We examined the kinetics of histone H3 phosphorylation and dephosphorylation in response to mitogen stimulation in wild-type mouse embryonic fibroblasts and compared this with mouse embryonic fibroblasts derived from the DUSP1 ⁄ MAP kinase phosphatase (MKP)-1) ⁄ ) knockout mouse in which DUSP1 has been deleted by homologous recombination [44]
It is clear from this update on MKP function that one of the main unanswered questions is a detailed mechanistic understanding of how MKPs maintain spatial control of MAPK signalling

Summary

Introduction

Mitogen-activated protein kinases (MAPKs) are components of highly conserved signal transduction pathways, which act in a concerted manner to determine both physiological and pathological responses to a wide variety of extracellular and intracellular stimuli [1,2]. Based on structural similarity between the MAPK-binding domain of DUSP10 ⁄ MKP-5 and DUSP16 ⁄ MKP-7, the authors suggest that this mechanism may be a conserved feature of the p38 and JNK-specific phosphatases DUSP10 ⁄ MKP-5, DUSP8 (M3 ⁄ 6) and DUSP16 ⁄ MKP7 and may underpin their ability to interact with these kinases rather than with ERK [30]. ERK is dephosphorylated extremely rapidly in certain cell lines following growth factor stimulation or MKK inhibition [54,55], indicating that constitutive Ser ⁄ Thr phosphatase activity (mediated by enzymes such as PP1 and PP2A) that act at multiple levels in MAPK cascades [56], coupled with tight control of signal flux through MAPKKK and MKK [57], are major mechanisms for controlling the intensity of MAPK output. Many MKPs are characteristically expressed at low levels under basal conditions and are rapidly induced by

C Crosstalk

Summary