S-adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouse and human hepatocytes

ABSTRACT Smk1 is a meiosis-specific mitogen-activated protein kinase (MAPK) in Saccharomyces cerevisiae that couples spore morphogenesis to the completion of chromosome segregation. Similar to other MAPKs, Smk1 is controlled by phosphorylation of a threonine (T) and a tyrosine (Y) in its activation loop. However, it is not activated by a dual-specificity MAPK kinase. Instead, T207 in Smk1's activation loop is phosphorylated by the cyclin-dependent kinase (CDK)-activating kinase (Cak1), and Y209 is autophosphorylated in an intramolecular reaction that requires the meiosis-specific protein Ssp2. In this study, we show that Smk1 is catalytically inert unless it is bound by Ssp2. While Ssp2 binding activates Smk1 by a mechanism that is independent of activation loop phosphorylation, binding also triggers autophosphorylation of Y209 in Smk1, which, along with Cak1-mediated phosphorylation of T207, further activates the kinase. Autophosphorylation of Smk1 on Y209 also appears to modify the specificity of the MAPK by suppressing Y kinase and enhancing S/T kinase activity. We also found that the phosphoconsensus motif preference of Ssp2/Smk1 is more extensive than that of other characterized MAPKs. This study therefore defines a novel mechanism of MAPK activation requiring binding of an activator and also shows that MAPKs can be diversified to recognize unique phosphorylation motifs.

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The MKK7 Gene Encodes a Group of c-Jun NH2-Terminal Kinase Kinases

Molecular and Cellular Biology ◽

10.1128/mcb.19.2.1569 ◽

1999 ◽

Vol 19 (2) ◽

pp. 1569-1581 ◽

Cited By ~ 117

Author(s):

Cathy Tournier ◽

Alan J. Whitmarsh ◽

Julie Cavanagh ◽

Tamera Barrett ◽

Roger J. Davis

Keyword(s):

Protein Kinase ◽

Protein Kinases ◽

Cultured Cells ◽

Biochemical Properties ◽

Mitogen Activated Protein Kinase ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Extracellular Stimuli ◽

Jnk Activation

ABSTRACT The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (α, β, and γ isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7α isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7α isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7β and MKK7γ isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that theMKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

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Dual Specificity Mitogen-Activated Protein Kinase Kinase 2

10.32388/oq14z6 ◽

2020 ◽

Author(s):

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

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Mitogen-activated protein kinase kinase 1 (MKK1) is negatively regulated by threonine phosphorylation

Molecular and Cellular Biology ◽

10.1128/mcb.14.3.1594-1602.1994 ◽

1994 ◽

Vol 14 (3) ◽

pp. 1594-1602

Author(s):

A J Rossomando ◽

P Dent ◽

T W Sturgill ◽

D R Marshak

Keyword(s):

Protein Kinase ◽

Phosphorylation Site ◽

Mitogen Activated Protein Kinase ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Protein Kinase Cascade ◽

Protein Kinase Kinase

Mitogen-activated protein kinase kinase 1 (MKK1), a dual-specificity tyrosine/threonine protein kinase, has been shown to be phosphorylated and activated by the raf oncogene product as part of the mitogen-activated protein kinase cascade. Here we report the phosphorylation and inactivation of MKK1 by phosphorylation on threonine 286 and threonine 292. MKK1 contains a consensus phosphorylation site for p34cdc2, a serine/threonine protein kinase that regulates the cell division cycle, at Thr-286 and a related site at Thr-292. p34cdc2 catalyzes the in vitro phosphorylation of MKK1 on both of these threonine residues and inactivates MKK1 enzymatic activity. Both sites are phosphorylated in vivo as well. The data presented in this report provide evidence that MKK1 is negatively regulated by threonine phosphorylation.

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Mitogen-activated protein kinase phosphatase 2 regulates histone H3 phosphorylation via interaction with vaccinia-related kinase 1

Molecular Biology of the Cell ◽

10.1091/mbc.e12-06-0456 ◽

2013 ◽

Vol 24 (3) ◽

pp. 373-384 ◽

Cited By ~ 18

Author(s):

Min-Woo Jeong ◽

Tae-Hong Kang ◽

Wanil Kim ◽

Yoon Ha Choi ◽

Kyong-Tai Kim

Keyword(s):

Protein Kinase ◽

Histone H3 ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

H3 Phosphorylation ◽

Dual Specificity ◽

Selective Interaction ◽

M Phase ◽

Mitogen Activated Protein ◽

Histone H3 Phosphorylation

Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate MAP kinase signaling. However, MKP2 functions are still largely unknown. In this study, we showed that MKP2 could regulate histone H3 phosphorylation under oxidative stress conditions. We found that MKP2 inhibited histone H3 phosphorylation by suppressing vaccinia-related kinase 1 (VRK1) activity. Moreover, this regulation was dependent on the selective interaction with VRK1, regardless of its phosphatase activity. The interaction between MKP2 and VRK1 mainly occurred in the chromatin, where histones are abundant. We also observed that the protein level of MKP2 and its interaction with histone H3 increased from G1 to M phase during the cell cycle, which is similar to the VRK1 profile. Furthermore, MKP2 specifically regulated the VRK1-mediated histone H3 phosphorylation at M phase. Taken together, these data suggest a novel function of MKP2 as a negative regulator of VRK1-mediated histone H3 phosphorylation.

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