Role of the JIP4 Scaffold Protein in the Regulation of Mitogen-Activated Protein Kinase Signaling Pathways

Kelkar, Nyaya; Standen, Claire L.; Davis, Roger J.

doi:10.1128/mcb.25.7.2733-2743.2005

Cited by 161 publications

(204 citation statements)

References 37 publications

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“…The JLP protein has several functional domains, including two leucine zipper domains, a JNK binding domain, and a C-terminal domain, which mediate protein-protein interactions (3,27). To map the region of JLP that interacts with PLK1, HEK293T cells were transfected with S-tagged WT and domain mutants of JLP (Fig.…”

Section: Resultsmentioning

confidence: 99%

JNK-associated Leucine Zipper Protein Functions as a Docking Platform for Polo-like Kinase 1 and Regulation of the Associating Transcription Factor Forkhead Box Protein K1

Ramkumar

Lee

Moradian

et al. 2015

Journal of Biological Chemistry

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Background:The role of JLP in cell signaling is not well defined. Results: JLP interacts with PLK1 and FOXK1 during mitosis, and ablation of JLP leads to increased FOXK1 protein levels. Conclusion: Phosphorylation of JLP by PLK1 recruits FOXK1, whose expression and activity is regulated by JLP. Significance: Our results suggest a novel mechanism of regulation of FOXK1 by associating with JLP-PLK1 complex.

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Section: Resultsmentioning

confidence: 99%

JNK-associated Leucine Zipper Protein Functions as a Docking Platform for Polo-like Kinase 1 and Regulation of the Associating Transcription Factor Forkhead Box Protein K1

Ramkumar

Lee

Moradian

et al. 2015

Journal of Biological Chemistry

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“…JLP is a member of the JIP (JNK-interacting protein) family, which provides a scaffolding function for the JNK/p38 MAPK signaling module. JLP is encoded by the JIP4 gene, which generates three distinct splice variants, namely, JLP, JIP4, and SPAG9 (32). Specifically, JLP was identified as a scaffold protein involved in the p38 MAPK signaling pathway to bring p38 MAPK together with its upstream kinases (21).…”

Section: Discussionmentioning

confidence: 99%

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

Andō

Uemura

Kuzuya

et al. 2011

Journal of Biological Chemistry

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Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with A␤ 42 decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherinbased synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by A␤ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.Alzheimer disease (AD) 2 is pathologically characterized by the presence of amyloid ␤-peptide (A␤) and neurofibrillary tangles in the neocortex and hippocampus. Insoluble A␤ fibrillar aggregates found in senile plaques have long been considered to cause the neurodegeneration of AD. On the other hand, synaptic loss is another pathological hallmark of AD, which strongly correlates with the severity of cognitive impairment better than senile plaques or neurofibrillary tangles (1). Interestingly, recent studies from AD mouse models have shown that learning impairment and synaptic dysfunction become apparent before the formation of plaques, suggesting the hypothesis that soluble A␤ causes "synaptic failure" before plaques develop and neuron death occurs (2). Converging lines of evidence suggest that natural soluble A␤ oligomers trigger synaptic loss (3). Thus, in addition to the investigation of molecular mechanisms, which develop senile plaques and neurofibrillary tangles, research focusing on synaptic dysfunction is important to clarify the earliest pathology in AD.Presenilin (PS) 1/2 is the essential catalytic component of ␥-secretase proteolytic complex (4, 5), which is responsible for the final cleavage of amyloid precursor protein to generate A␤ peptides. Mutations in PS1 have been known as the most common cause of autosomal dominant familial Alzheimer disease (6 -8). Interestingly, PS1 binds to N-cadherin, which is an essential molecule for synaptic contact and is abundantly localized in hippocampal synapses ...

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“…30,31 However, there are relatively few known p38MAPK scaffolds, with JIP2 and JIP4 reported to bind to and possibly regulate localisation of p38MAPK activity. [32][33][34] Osmosensing scaffold for MEKK3 (OSM) has also been shown to act as a p38MAPK scaffold. 35 OSM responds to osmotic stress by recruiting p38MAPK and Rac to membrane ruffles, wherein they co-operate to reorganise the actin cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK

et al. 2009

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Most cells undergo apoptosis through the intrinsic pathway. This is dependent on mitochondrial outer membrane permeabilisation (MOMP), which is mediated by the pro-apoptotic Bcl-2 family proteins, Bax and Bak. During apoptosis, Bax translocates from the cytosol to the outer mitochondrial membrane (OMM), wherein it contributes to the formation of pores to release cytochrome-c. However, it remains unclear whether Bax translocation is sufficient to bring about MOMP or whether Bax requires further signals on the OMM to be fully activated. We have previously shown that during mammary epithelial cell anoikis, Bax translocation does not commit cells to MOMP and detached cells are rescued if survival signals from the extracellular matrix (ECM) are restored. These findings implied that a second signal is required for mitochondrial Bax to fully activate and cause MOMP. We now identify p38MAPK (mitogen-activated protein kinase) as this necessary signal to activate Bax after its translocation to mitochondria. The inhibition of p38MAPK did not prevent Bax translocation, but its activity was required for mitochondrial Bax to bring about MOMP. p38MAPK was activated and recruited to a high molecular weight mitochondrial complex after loss of ECM attachment. Artificially targeting p38MAPK to the OMM increased the kinetics of anoikis, supporting a requirement for its mitochondrial localisation to regulate Bax activation and drive commitment to apoptosis. Metazoan cells are pre-programmed to undergo apoptosis in response to becoming damaged or losing essential survival signals. Apoptosis in response to these cellular stresses is initiated through the intrinsic, or mitochondrial, pathway. 1 During intrinsic apoptosis, mitochondrial outer membrane permeabilisation (MOMP) results in the release of proteins, such as cytochrome-c and second mitochondrial activator of caspases (Smac)/Diablo, which activate the caspases to drive cell death. The release of cytochrome-c and Smac/Diablo is an extremely rapid event, with mitochondria throughout the cell releasing their contents within a few minutes of MOMP first commencing. 2,3 The resulting activation of caspases occurs immediately and cell death is complete within a few minutes. After MOMP, cells rapidly lose viability, even if caspase activation is inhibited. Thus, MOMP represents a point at which cells cannot be rescued from an apoptotic fate.The Bcl-2 family of proteins regulates MOMP. 4 These are characterised by a number of shared regions of sequence homology, the Bcl-2 Homology (BH) domains. Pro-survival members, such as Bcl-2 and Bcl-X L , share BH-domains 1-4. In contrast, the pro-apoptotic proteins, Bax and Bak, only posses BH-domains 1, 2 and 3. A third group of Bcl-2 proteins are the BH3-only proteins, which function by sensing survival and stress signals, and transmit these to the pro-and antiapoptotic multi-domain proteins. 5 The multi-domain proapoptotic proteins, Bax and Bak, are expressed in virtually all tissues, and are absolutely required for MOMP to occur. 6 Cells deriv...

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Role of the JIP4 Scaffold Protein in the Regulation of Mitogen-Activated Protein Kinase Signaling Pathways

Cited by 161 publications

References 37 publications

JNK-associated Leucine Zipper Protein Functions as a Docking Platform for Polo-like Kinase 1 and Regulation of the Associating Transcription Factor Forkhead Box Protein K1

JNK-associated Leucine Zipper Protein Functions as a Docking Platform for Polo-like Kinase 1 and Regulation of the Associating Transcription Factor Forkhead Box Protein K1

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK

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