Mitogen-activated protein kinase phosphatase: a negative regulator of the mitogen-activated protein kinase cascade

doi:10.1016/S0014-2999(98)00857-7

European Journal of Pharmacology

Volume 365, Issue 1, 15 January 1999, Pages 1-7

https://doi.org/10.1016/S0014-2999(98)00857-7 Get rights and content

Abstract

Mitogen-activated protein kinases (MAPKs) are activated by various stimuli, such as growth factors, cytokines, or stress, and are considered to be important mediators in intracellular signal transduction networks. The dual-specificity kinases, MAPK kinases (MKKs), which phosphorylate the TXY motif in the catalytic domain of MAPKs, can cause the activation of MAPKs. Recently, a family of dual-specificity phosphatases has been identified, members of which are able to dephosphorylate and inactivate MAPKs. The studies cited in this review have revealed that these MAPK phosphatases might play an important role in various cellular functions by downregulating the MAPK cascade.

Introduction

Activation of the mitogen-activated protein kinase (MAPK) cascade is considered to play a key role in signal transduction pathways activated by various stimuli including growth factors, vasoactive peptides and cytokines. Three major subclasses of MAPKs, namely, extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK), and homologue of budding yeast HOG1 (p38 MAPK), have been identified. Full activation of these MAPKs requires the phosphorylation of both the threonine and tyrosine residues of the TXY motif in the catalytic domain by upstream dual-specificity kinases, termed MAPK kinases (MKK-1/2, MKK-3/6, and MKK-4 for ERK, p38 MAPK, and JNK/SAPK, respectively) (Guan, 1994; Seger and Krebs, 1995; Denhard, 1996; Kyriakis and Avruch, 1996; Robinson and Cobb, 1997). In order to understand the importance of MAPKs in subsequent cellular functions, it is necessary to clarify the mechanisms responsible for the activation and inactivation of MAPKs. For example, in PC12 cells, transient activation of ERK was found to cause cell proliferation, whereas sustained activation of ERK was shown to induce cell differentiation (Marshall, 1995), indicating the importance of the inactivation of ERK in the regulation of cellular functions. Recently, a family of dual-specificity protein phosphatases, which can dephosphorylate both phospho-threonine and phospho-tyrosine residues, has been identified and termed MAPK phosphatases (Guan, 1994; Keyse, 1995). In this review, we will discuss the general biochemical characters and physiological significance of these phosphatases.

Section snippets

Identification of a family of MAPK phosphatases

A highly conserved sequence, (I/V)HCXAGXXR(S/T)G, in a family of protein tyrosine phosphatase (PTPase) has been found to be essential for phosphatase activity (Denu et al., 1996) and is considered to determine the specificity of PTPase for the phospho-tyrosine residue in substrates. In 1991, Guan et al. used the conserved active site sequence of PTPase to search a database and cloned a new gene from vaccinia virus, vaccinia virus H1 phosphatase (VH1), which encodes a 20-kDa PTPase (Guan et al.,

Substrate specificity of MAPK phosphatases

In order to understand the role of MAPK phosphatases in various cellular functions, it is necessary to clarify the substrate specificity of these MAPK phosphatases for members of the MAPK family, namely, ERK, JNK/SAPK, or p38 MAPK. The recombinant phosphatases show low substrate specificity for MAPKs in vitro, except for MKP-3/pyst1/rVH6 and hVH-5/M3-6, which are highly specific in their inactivation of ERK or JNK/SAPK and p38 MAPK, respectively (Chu et al., 1996; Groom et al., 1996; Muda et

Mechanism of the inactivation of ERK by MAPK phosphatases and other phosphatases

Upon activation, ERK translocates to the nucleus (Chen et al., 1992; Gonzalez et al., 1993; Lenormand et al., 1993; Zheng and Guan, 1994), where it can phosphorylate transcriptional factors, such as Elk-1, and induce the expression of various genes (Gille et al., 1992; Marais et al., 1993; Nakajima et al., 1993; Gille et al., 1995; Hill and Treisman, 1995; Sugimoto et al., 1997). Since MKP-1 is reported to be mainly expressed in the nucleus, a simple model is evoked by which the growth

Mechanism of the induction and physiological significance of MAPK phosphatases

As discussed above, MKP-1 has been identified as an immediate early gene (Charles et al., 1992). Various stimuli, such as growth factors, stress, phorbor ester, and vasoactive peptides, have been reported to induce mRNA expression (Charles et al., 1992; Keyse and Emslie, 1992; Duff et al., 1993; Zheng and Guan, 1993; Sugimoto et al., 1997). The promoter sequence of the MKP-1 gene contains the AP-1 and CRE sites (Kwak et al., 1994), which respond to protein kinase C and Ca²⁺/cAMP signalling

Concluding remarks

We have reviewed recent progress in research into the MAPK phosphatases, which dephosphorylate and inactivate members of the MAPK family. MAPK phosphatases have been identified in species ranging from yeast (Doi et al., 1994) to humans, which suggests that the mechanisms for inactivation of MAPKs are highly conserved, as are the mechanisms for their activation. However, there are still questions to be answered, namely, (1) the precise mechanisms of the transcriptional activation of MAPK

References (71)

D.R. Alessi et al.
Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines
Curr. Biol.
(1995)
D. Bokemeyer et al.
Induction of mitogen-activated protein kinase phosphatase 1 by the stress activated protein kinase signalling pathway but not by extracellular signal-regulated kinase in fibroblasts
J. Biol. Chem.
(1996)
J.M. Brondello et al.
The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44 MAPK cascade
J. Biol. Chem.
(1997)
D. Brunner et al.
A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine signalling pathways
Cell
(1994)
S.J. Cook et al.
Regulation of mitogen-activated protein kinase phosphatase-1 expression by extracellular signal-regulated kinase-dependent and Ca2+-dependent signal pathway in Rat-1 cells
J. Biol. Chem.
(1997)
Y. Chu et al.
The mitogen-activated protein kinase phosphatase PAC1, MKP-1, and MKP-2 have unique substrate specificities and deduced activity in vivo toward the ERK2 sevenmaker mutation
J. Biol. Chem.
(1996)
J.M. Denu et al.
Form and function in protein dephosphorylation
Cell
(1996)
J.L. Duff et al.
Angiotensin II induces 3CH134. A protein–tyrosine phosphatase, in vascular smooth muscle cells
J. Biol. Chem.
(1993)
J.L. Duff et al.
Mitogen-activated protein kinase is regulated by the MAP kinase phosphatase (MKP-1) in vascular smooth muscle cells. Effect of actinomycin D and antisense oligonucleotides
J. Biol. Chem.
(1995)
C.C. Franklin et al.
Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells
J. Biol. Chem.
(1997)

K.L. Guan

The mitogen-activated protein kinase signal transduction pathway: from the cell surface to the nucleus

Cell Signal

(1994)

K.L. Guan et al.

Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase

J. Biol. Chem.

(1995)

C.S. Hill et al.

Transcriptional regulation by extracellular signals: mechanisms and specificity

Cell

(1995)

D.D. Hirsch et al.

Mitogen-activated protein kinase phosphatase inactivates stress-activated protein kinase in vivo

J. Biol. Chem.

(1997)

T. Ishibashi et al.

A novel dual specificity phosphatase induced by serum stimulation and heat shock

J. Biol. Chem.

(1994)

S.M. Keyse

An emerging family of dual specificity MAP kinase phosphatases

Biochem. Biophys. Acta

(1995)

S.P. Kwak et al.

Multiple dual specificity protein tyrosine phosphatases are expressed and regulated differentially in liver cell lines

J. Biol. Chem.

(1995)

S.P. Kwak et al.

Isolation and characterization of human dual specificity protein–tyrosine phosphatase gene

J. Biol. Chem.

(1994)

J.M. Kyriakis et al.

Sounding the alarm: protein kinase cascades activated by stress and inflammation

J. Biol. Chem.

(1996)

R. Marais et al.

The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain

Cell

(1993)

C.J. Marshall

Specificity of receptor tyrosine kinase signalling: transient vs. sustained extracellular signal-regulated kinase activation

Cell

(1995)

A. Misra-Press et al.

A novel mitogen activated protein kinase phosphatase. Structure, expression, and regulation

J. Biol. Chem.

(1995)

R.J. Mourey et al.

A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neural differentiation

J. Biol. Chem.

(1996)

M. Muda et al.

MKP-3, a novel cytosolic protein tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase

J. Biol. Chem.

(1996)

M. Muda et al.

The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases

J. Biol. Chem.

(1996)

M. Muda et al.

Molecular cloning and functional characterization of a novel mitogen-activated protein phosphatase, MKP-4

J. Biol. Chem.

(1997)

M. Muda et al.

The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzyme specificity

J. Biol Chem.

(1998)

M.J. Robinson et al.

Mitogen-activated protein kinase pathways

Curr. Opin. Cell. Biol.

(1997)

T. Sugimoto et al.

A trial natriuretic peptide induces the expression of MKP-1, a mitogen-activated protein phosphatase, in glomerular mesangial cells

J. Biol. Chem.

(1996)

T. Sugimoto et al.

The calcium/calmodulin-dependent protein phosphatase calcineurin is the major Elk-1 phosphatase

J. Biol. Chem.

(1997)

H. Sun et al.

MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo

Cell

(1993)

M. Togawa et al.

Beraprast sodium, an analogue of prostacyclin, induces the expression of mitogen-activated protein kinase phosphatase and inhibits the proliferation of cultured mesangial cells

Eur. J. Pharmacol.

(1997)

N.K. Tonks et al.

From form to function: signalling by protein tyrosine phosphatases

Cell

(1996)

J. Wu et al.

Rapid deactivation of MAP kinase in PC12 cells occurs independently of induction of phosphatase MKP-1

FEBS Lett.

(1994)

C.F. Zheng et al.

Dephosphorylation and inactivation of mitogen-activated protein kinase by a mitogen-induced Thr/Tyr protein phosphatase

J. Biol. Chem.

(1993)

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ReviewMitogen-activated protein kinase phosphatase: a negative regulator of the mitogen-activated protein kinase cascade

Abstract

Introduction

Section snippets

Identification of a family of MAPK phosphatases

Substrate specificity of MAPK phosphatases

Mechanism of the inactivation of ERK by MAPK phosphatases and other phosphatases

Mechanism of the induction and physiological significance of MAPK phosphatases

Concluding remarks

Curr. Biol.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell Signal

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol Chem.

Curr. Opin. Cell. Biol.

J. Biol. Chem.

J. Biol. Chem.

Cell

Eur. J. Pharmacol.

Cell

FEBS Lett.

J. Biol. Chem.

Review
Mitogen-activated protein kinase phosphatase: a negative regulator of the mitogen-activated protein kinase cascade