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