Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway

Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
The EMBO Journal (Impact Factor: 10.43). 12/2004; 23(24):4780-91. DOI: 10.1038/sj.emboj.7600489
Source: PubMed


Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), which is regulated by protein stability. However, its function is unknown and no physiological substrates for ERK3 have yet been identified. Here we demonstrate a specific interaction between ERK3 and MAPK-activated protein kinase-5 (MK5). Binding results in nuclear exclusion of both ERK3 and MK5 and is accompanied by ERK3-dependent phosphorylation and activation of MK5 in vitro and in vivo. Endogenous MK5 activity is significantly reduced by siRNA-mediated knockdown of ERK3 and also in fibroblasts derived from ERK3-/- mice. Furthermore, increased levels of ERK3 protein detected during nerve growth factor-induced differentiation of PC12 cells are accompanied by an increase in MK5 activity. Conversely, MK5 depletion causes a dramatic reduction in endogenous ERK3 levels. Our data identify the first physiological protein substrate for ERK3 and suggest a functional link between these kinases in which MK5 is a downstream target of ERK3, while MK5 acts as a chaperone for ERK3. Our findings provide valuable tools to further dissect the regulation and biological roles of both ERK3 and MK5.

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Available from: Stephen M Keyse, Oct 10, 2015
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    • "Previous data suggested that MK5 is not a physiological substrate for p38 in vivo,67) because the stimuli that activate the p38 pathway fail to activate MK5, and the binding of endogenous p38 to MK5 is weaker than its interaction with other established substrates, namely, MK2 and MK3. Interestingly, it has been recently demonstrated that MK5 strongly interacts with and is activated by ERK3.67,68) Given this very basic mechanism for the cellular neurophysiological cascades, the MAPK4 gene could influence the intracellular signaling pathways leading to the comorbidity of psychosis and addiction. "
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    ABSTRACT: Objective It was previously suggested that the malic enzyme 2 (ME2) as the candidate gene for psychosis in fine mapping of chromosome 18q21. Chromosome 18q21 is also one of the possible regions that can contribute to addiction. Methods We performed a pilot study for discovering candidate gene of chromosome 18q21 in the methamphetamine abusers for elucidating the candidate gene for methamphetamine addiction leading to psychosis. We have selected 30 unrelated controls (16 males, 14 females; age=59.8±10.4) and 37 male methamphetamine abusers (age=43.3±7.8). We analyzed 20 single nucleotide polymorphisms (SNPs) of 7 neuronal genes in chromosome 18q21 for DNA samples that was checked for the data quality and genotype error. The association between the case-control status and each individual SNP was measured using multiple logistic regression models (adjusting for age and sex as covariates). And we controlled false discovery rate (FDR) to deal with multiple testing problem. Results We found 3 significant SNPs of 2 genes in chromosome 18q21 (p-value<0.05; adjusting for age as covariate) in methamphetamine abusers compared to controls. We also found 2 significant SNPs of 1 gene (p-value<0.05; adjusting for age and sex as covariates) (rs3794899, rs3794901:MAPK4). Two SNPs in MAPK4 gene were significant in both statistical groups. Conclusion MAPK4, the gene for mitogen-activated protein kinase 4, is one of the final 6 candidate genes including ME2 in 18q12-21 in our previous finemapping for psychosis. Our results suggest that MAPK4 can be a candidate gene that contribute to the methamphetamine addiction leading to psychosis.
    Clinical Psychopharmacology and Neuroscience 04/2014; 12(1):54-64. DOI:10.9758/cpn.2014.12.1.54
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    • "DnaJC1 (=ERj1) can be phosphorylated in vitro by casein kinase-2, DnaJA3 (=TID1) is tyrosine-phosphorylated by Trk receptor tyrosine kinases, while DnaJC5 is phosphorylated by PKA on Ser-10 (Evans et al., 2001; Liu et al., 2005; Götz et al., 2009). Mitogen-activated protein-activated protein kinase 5 (MK5/PRAK) is a serine/threonine kinase that is activated by the atypical mitogen-activated protein kinases ERK3 and ERK4 and by the conventional mitogen-activated protein kinase p38 (Schumacher et al., 2004; Seternes et al., 2004; Aberg et al., 2006; Kant et al., 2006). The activity of MK5 is also stimulated by cAMPdependent protein kinase/protein kinase A (Gerits et al., 2007). "
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    ABSTRACT: Heat shock protein 40 (Hsp40) acts as a co-chaperone with Hsp70 to promote protein folding, protein transport and degradation. The human Hsp40 family contains more than 40 members, some of which can exist as phosphoproteins in the cell. However, little is known about the protein kinases responsible for their phosphorylation and the functional relevance of this post-translational modification remains elusive. Here we show that Hsp40/DnaJB1 is an in vitro and in vivo substrate for the mitogen-activated protein kinase-activated protein kinase 5 (MK5). MK5 and Hsp40/DnaJB1 form complexes in cells and this interaction is accomplished by the C-terminal regions of both proteins. MK5 can phosphorylate Hsp40/DnaJB1 at several residues in vitro. Studies with specific phosphoantibodies indicate that MK5 phosphorylates Hsp40/DnaJB1 in vivo at Ser-149 or/and Ser-151 and Ser-171 in the C-terminal domain of Hsp40/DnaJB1. MK5 modestly stimulates the ATP hydrolyse activity of Hsp40/Hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by Hsp40/DnaJB1.
    The international journal of biochemistry & cell biology 12/2013; 47(1). DOI:10.1016/j.biocel.2013.11.004 · 4.05 Impact Factor
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    • "In vitro studies have shown that ERK2 can phosphorylate MK5 (Ni et al. , 1998 ), but the results from Srivastav and coworkers argue against an in vivo interaction between these two kinases. In accordance, no interaction between ERK2 and MK5 was detected by yeast two-hybrid and GST-pull down assays (Seternes et al. , 2004 ). Interaction occurs preferentially with the unique C-terminal fragment of MK5, although binding sites for a few partners have been mapped (Table 1 ). "
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    ABSTRACT: Abstract Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen-and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions and possible implications of MK5/PRAK in malignant and non-malignant diseases.
    Biological Chemistry 05/2013; 394(9). DOI:10.1515/hsz-2013-0149 · 3.27 Impact Factor
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