A conserved motif in JNK/p38-specific MAPK phosphatases as a determinant for JNK1 recognition and inactivation

Liu, Xin; Zhang, Chen-Song; Lu, Chang; Lin, Sheng-Cai; Wu, Jiawei; Wang, Zhixin

doi:10.1038/ncomms10879

Cited by 40 publications

(54 citation statements)

References 72 publications

(84 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of the rhodanese domains in MKP1 and MKP5 in recruiting ERK2 and p38␣ is well-known: by mimicking a so-called docking motif, this surface enables strong interactions with several MAPKs (79). However, the docking site of JNK cannot bind rhodanese domains, so phosphatases targeting JNK bind in alternative ways (via their catalytic domain or by docking motifs, as observed in MKP5 and MKP7 [80,81]). In vivo studies suggest that MKP1 is not required for growth factor signaling; however, it is essential for immune cell activation, as MKP1 Ϫ/Ϫ mice show immune defects (82).…”

Section: Phosphatases and Feedback Mechanisms In Control Of Jnk Activitymentioning

confidence: 99%

“…signed to include docking domain peptides suggested that the FxFP site of JNKs is still functional (201); recent structural studies indeed suggest that this site mediates JNK1 interaction with the dual-specificity phosphatase MKP7 (81). Despite these alternative modes of interactions with the MAPKs, most JNK interactors use typical D-motifs to partner with JNKs (80).…”

Section: Jnk Recognition Of Its Partner Regulators and Substrates Docmentioning

confidence: 99%

See 1 more Smart Citation

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

383

350

View full text Add to dashboard Cite

SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

show abstract

Section: Phosphatases and Feedback Mechanisms In Control Of Jnk Activitymentioning

confidence: 99%

Section: Jnk Recognition Of Its Partner Regulators and Substrates Docmentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

383

350

View full text Add to dashboard Cite

show abstract

“…JNK1δ displays a large deletion (of about 80 residues), lacking exons 6, 7 and 8. It does not contain the F-helix, shown to be crucial for kinases structural stability [42], nor the MAPK insert, involved in the binding of the phosphatase MKP7 [44] (Fig. 2).…”

Section: Properties Of the Orphan Transcriptsmentioning

confidence: 99%

“…Residues comprising the catalytic site were defined from the complex between human JNK3 and adenosine mono-phosphate (PDB code: 4KKE, resolution: 2.2Å), as those located less than 6Å away from the ligand. Residues comprising the D-site and the F-site were defined from the complexes between human JNK1 and the scaffolding protein JIP-1 (PDB code: 1UKH, resolution: 2.35 A [63]) and the catalytic domain of MKP7 (PDB code: 4YR8, resolution: 2.4 A [44]), respectively. They were detected as displaying a change in relative solvent accessibility >1Å 2 upon binding.…”

Section: Analysis Of Jnk Tertiary Structuresmentioning

confidence: 99%

Transcripts’ evolutionary history and structural dynamics give mechanistic insights into the functional diversity of the JNK family

Ait-hamlat

Zea

Labeeuw

et al. 2017

Preprint

View full text Add to dashboard Cite

8Alternative splicing (AS), by producing several transcript isoforms from the same gene, has the po-9 tential to greatly expand the proteome in eukaryotes. Its deregulation has been associated to the 10 development of various diseases, including cancer. Although the AS mechanisms are well described 11 at the genomic level, little is known about the contribution of AS to protein evolution and the im-12 pact of AS at the level of the protein structure. Here, we address both issues by reconstructing the isoforms. PhyloSofS has broad applicability and can be used, for example, to study transcripts diver-26 sity between di erent individuals (e.g. patients a ected by a particular disease). It is freely available 27 at www.lcqb.upmc.fr/PhyloSofS. 28. CC-BY-NC 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/119891 doi: bioRxiv preprint first posted online Mar. 23, 2017; Evolution and structural impact of alternative splicing for JNKs. 3 Author Summary 29Alternative splicing (AS) is a eukaryotic regulatory process by which multiple proteins are produced 30 from the same gene. Although the mechanisms of AS have been extensively described at the level of 31 the gene, little is known about its contribution to protein evolution and its impact on the shape and 32 motions of the produced isoforms. Here, we address both issues computationally, focusing our study structures. We show that an ancient ASE having significant functional outcome induces very subtle 37 changes on the structural dynamics of the protein and we identify the residues likely responsible 38 for the functional change. We highlight a new isoform, not previously documented, and explore its 39 motions in solution. We propose that it may play a role in the cell and serve as a therapeutic target. 40Finally, we link the evolutionary conservation of transcripts to sequence and structural properties.

show abstract

“…There are 3 well‐defined MAPK pathways: ERK‐1/2, JNK‐1/2, and p38 (12). MAPK signaling efficiency and specificity are modulated by protein–protein interactions between individual MAPKs and the docking motifs in cognate binding partners (13). Important signaling pathways regulating responses of the cells to the infection and stress are via MAPKs (14).…”

mentioning

confidence: 99%

Complement‐induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction

et al. 2017

View full text Add to dashboard Cite

Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo. In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in

show abstract

A conserved motif in JNK/p38-specific MAPK phosphatases as a determinant for JNK1 recognition and inactivation

Cited by 40 publications

References 72 publications

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Transcripts’ evolutionary history and structural dynamics give mechanistic insights into the functional diversity of the JNK family

Complement‐induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction

Contact Info

Product

Resources

About