Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Jun NH2-terminal kinase (JNK) is activated during obesity. One consequence of obesity is that JNK phosphorylates the adapter protein insulin receptor substrate 1 (IRS-1) on Ser 307 and inhibits signaling by the insulin receptor. JNK can therefore cause peripheral insulin resistance during obesity and may contribute to the development of type 2 diabetes. Here we report that the JNK-interacting protein 1 (JIP1) scaffold protein, which binds components of the JNK signaling module, is essential for JNK activation in the adipose tissue of obese mice. These data identify JIP1 as a novel molecular target for therapeutic intervention in the development of obesity.
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PMID:An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. 1531 24

We recently demonstrated that the cytomegalovirus (CMV) immediate-early 1 (IE1) protein induces transcription of the gene encoding the RelB NF-kappaB subunit. The mechanism of this activation has been explored here. We report that the induction of the relB promoter by IE1 protein is mediated via activation of JNK and AP-1. The region controlling relB promoter induction was mapped to the upstream approximately 600-bp region between -1694 and -1096 bp. IE1 stimulated AP-1 activity in NIH 3T3 cells. Competition electrophoretic mobility shift assay (EMSA) confirmed the presence of one bona fide AP-1 element centered at -1503 bp. Introduction of a G-to-C mutation in the AP-1 binding site within the distal region of the relB promoter eliminated its activation by IE1 in both NIH 3T3 fibroblasts and vascular smooth muscle cells (SMCs). Supershift EMSA identified c-Jun, Fra-2, and c-Fos in AP-1 binding complexes in IE1 transfected NIH 3T3 cells. IE1 induced c-Jun phosphorylation, and treatment with SP600125, a selective JNK inhibitor, as well as overexpression of JNK-binding domain of JIP1, blocked IE1-mediated induction of AP-1 and relB promoter activity in NIH 3T3 cells and SMCs. Ectopic expression of c-Jun plus Fra-2, but not c-Fos, induced relB promoter activity. The relB promoter has two proximal NF-kappaB elements, and c-Jun/Fra-2 worked in synergy with p50/p65 NF-kappaB complexes. Overall, these findings demonstrate for the first time the role of AP-1 in transcriptional regulation of a gene encoding an NF-kappaB subunit, and its involvement in induction of RelB activity by the CMV IE1 protein.
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PMID:Induction of the RelB NF-kappaB subunit by the cytomegalovirus IE1 protein is mediated via Jun kinase and c-Jun/Fra-2 AP-1 complexes. 1559 5

The c-Jun NH2-terminal kinase (JNK)-interacting protein (JIP) group of scaffold proteins (JIP1, JIP2, and JIP3) can interact with components of the JNK signaling pathway and potently activate JNK. Here we describe the identification of a fourth member of the JIP family. The primary sequence of JIP4 is most closely related to that of JIP3. Like other members of the JIP family of scaffold proteins, JIP4 binds JNK and also the light chain of the microtubule motor protein kinesin-1. However, the function of JIP4 appears to be markedly different from other JIP proteins. Specifically, JIP4 does not activate JNK signaling. In contrast, JIP4 serves as an activator of the p38 mitogen-activated protein (MAP) kinase pathway by a mechanism that requires the MAP kinase kinases MKK3 and MKK6. The JIP4 scaffold protein therefore appears to be a new component of the p38 MAP kinase signaling pathway.
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PMID:Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. 1576 78

We examined if the relative expression of JNK-interacting protein 1 (JIP1) and phosphorylated c-Jun N-terminal kinase (JNK) regulates cell signaling and contributes to selective neuronal vulnerability in response to environmental stress. In clonal neuroblastoma cultures, stresses such as hypoxia, ischemia, Abeta peptides, and UV irradiation rapidly reduced JIP1 expression. JIP1 mRNA expression was also down-regulated by UV stress and was accompanied by increased JNK and c-Jun activation and cell death. JIP1 protein reduction was partially reversed both by inhibitors predominantly of caspase 3 and of the JNK pathway and resulted in significantly increased cell survival. Conversely, overexpression of JIP1 decreased both nuclear translocation of activated-JNK, and c-Jun phosphorylation induced by either UV irradiation, or the JNK upstream activators, MKK7 or MEKK1. Cell death was reduced about 50% compared to GFP-transfected controls. JIP1 overexpression did not facilitate either JNK expression or activation. In the normal, non-stressed human hippocampus and rat hippocampal organotypic cultures, JIP1 and JNK3 were inversely expressed with more JIP1 in CA2 and CA3 and less in CA1 neurons. In the human hippocampus, transient hypoxia/ischemia selectively spares neurons in CA2 and CA3 and induces death of neurons in the hippocampal CA1 subregion. In the cultures, ischemia reduced JIP1 expression and activated JNK, c-Jun, and caspase 3. Inhibitors of the JNK pathway, JNK activation directly and of caspase 3 activation each partially reversed these effects. Thus, under certain stress conditions, down-regulation of JIP1 expression makes neurons more susceptible to apoptosis, suggesting JIP may serve as an anti-apoptosis factor.
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PMID:JIP1 regulates neuronal apoptosis in response to stress. 1583 24

We have previously observed that metabolic oxidative stress-induced death domain-associated protein (Daxx) trafficking is mediated by the ASK1-SEK1-JNK1-HIPK1 signal transduction pathway. The relocalized Daxx from the nucleus to the cytoplasm during glucose deprivation participates in a positive regulatory feedback loop by binding to apoptosis signal-regulating kinase (ASK) 1. In this study, we report that Akt1 is involved in a negative regulatory feedback loop during glucose deprivation. Akt1 interacts with c-Jun NH(2)-terminal kinase (JNK)-interacting protein (JIP) 1, and Akt1 catalytic activity is inhibited. The JNK2-mediated phosphorylation of JIP1 results in the dissociation of Akt1 from JIP1 and subsequently restores Akt1 enzyme activity. Concomitantly, Akt1 interacts with stress-activated protein kinase/extracellular signal-regulated kinase (SEK) 1 (also known as MKK4) and inhibits SEK1 activity. Knockdown of SEK1 leads to the inhibition of JNK activation, JIP1-JNK2 binding, and the dissociation of Akt1 from JIP1 during glucose deprivation. Knockdown of JIP1 also leads to the inhibition of JNK activation, whereas the knockdown of Akt1 promotes JNK activation during glucose deprivation. Altogether, our data demonstrate that Akt1 participates in a negative regulatory feedback loop by interacting with the JIP1 scaffold protein.
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PMID:Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop. 1599 99

Viruses have to adjust to the host cell to guarantee their life cycle and survival. This aspect of the virus-host cell interaction is probably performed by viral proteins, such as serine-threonine kinases, that are present early during infection. Vaccinia virus has an early Ser-Thr kinase, B1R, which, although required for successful viral infection, is poorly characterized regarding its effects on cellular proteins, and thus, its potential contribution to pathogenesis is not known. Signaling by mitogen-activated protein kinase (MAPK) is mediated by the assembly of complexes between these kinases and the JIP scaffold proteins. To understand how vaccinia virus B1R can affect the host, its roles in the cellular signaling by MAPK complexes and c-Jun activation have been studied. Independently of its kinase activity, B1R can interact with the central region of the JIP1 scaffold protein. The B1R-JIP1 complex increases the amount of MAPK bound to JIP1; thus, MKK7 and TAK1 either bind with higher affinity or bind more stably to JIP1, while there is an increase in the phosphorylation state of JNK bound to JIP1. The functional consequence of these more stable interactions is an increase in the activity of transcription factors, such as c-Jun, that respond to these complexes. Furthermore, B1R is also able to directly phosphorylate c-Jun in residues different from those targeted by JNK and, thus, B1R can also cooperate by an independent route in c-Jun activation. Vaccinia virus B1R can thus modulate the signaling of pathways that respond to cellular stress.
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PMID:Vaccinia virus B1R kinase interacts with JIP1 and modulates c-Jun-dependent signaling. 1684 Mar 45

Jun N-terminal kinase (JNK) is a stress activated serine/threonine protein kinase that phosphorylates numerous cellular protein substrates including the transcription factors c-Jun and ATF2. In this study, we defined the kinetic mechanism for the active form of JNK2alpha2. Double reciprocal plots of initial rates versus concentrations of substrate revealed the sequential nature of the JNK2alpha2 catalyzed ATF2 phosphorylation. Dead-end JNK inhibitors were then used to differentiate ordered and random kinetic mechanisms for the reaction. A peptide inhibitor containing the homology JNK docking sequence for substrate recognition, derived from amino acid residues 153-163 of JNK-interacting protein 1 (JIP-1), inhibited JNK activity via competition with ATF2. This peptide functioned as a noncompetitive inhibitor against ATP. In contrast, the anthrapyrazolone compound, SP600125, exhibited competitive inhibition for ATP and noncompetitive inhibition against ATF2. Furthermore, binding of one substrate had no significant effect on the affinity for the other substrate. The data in this study are consistent with a kinetic mechanism for activated JNK2alpha2 in which (1) substrate binding is primarily due to the distal contacts in the JNK2alpha2 docking groove that allow the delivery of the substrate phosphorylation sequence into the catalytic center, (2) there is minimal allosteric communication between the protein-substrate docking site and the ATP binding site in the catalytic center for activated JNK2alpha2, and (3) the reaction proceeds via a random sequential mechanism.
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PMID:Kinetic characterization of human JNK2alpha2 reaction mechanism using substrate competitive inhibitors. 1739 42

T-lymphokine-activated killer cell-originated protein kinase (TOPK) is overexpressed in highly proliferating tumors such as leukemias and myelomas, and seems to play a key role in tumorigenesis or metastasis. However, the precise role and regulatory mechanism explaining the effects of TOPK on tumor cells still remain elusive. Here, we reported that TOPK regulates UVB-induced c-Jun-NH2-kinase 1 (JNK1) activity, and is essential for H-Ras-induced activator protein-1 activity and cell transformation. We showed that TOPK associated with and phosphorylated JNK1 following UVB irradiation in vitro or in vivo. Moreover, UVB-induced JNK1 activity was greatly augmented in mouse epidermal JB6 Cl41 cells that stably expressed TOPK cDNA. On the other hand, JNK1 activity was markedly attenuated by stable expression of small interfering RNA against TOPK in malignant melanoma RPMI 7951 cells. Interestingly, TOPK interacted with JNK-interacting protein 1 and caused an elevation of JNK-interacting protein 1 scaffolding activity, thereby enhancing JNK1 activity. Furthermore, JNK1 was required for TOPK-mediated activator protein-1 transcriptional activity and transformed foci induced by UVB or H-Ras. Taken together, these findings showed that TOPK positively modulated UVB-induced JNK1 activity and played a pivotal role in JNK1-mediated cell transformation induced by H-Ras. These studies might also provide a novel molecular mechanism for the role of TOPK in UVB-mediated skin carcinogenesis.
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PMID:T-lymphokine-activated killer cell-originated protein kinase functions as a positive regulator of c-Jun-NH2-kinase 1 signaling and H-Ras-induced cell transformation. 1754 98

The amyloid precursor protein (APP) is a type I transmembrane protein translocated to neuronal terminals, whose function is still unknown. The C-terminus of APP mediates its interaction with cellular adaptor and signaling proteins, some of which signal to the stress-activated protein kinase (SAPK) pathway. Here we show that ASK1, a MAPKKK that activates two SAPKs, c-Jun N-terminal-kinase (JNK) and p38, is present in a complex containing APP, phospho-MKK6, JIP1 and JNK1. In primary neurons deprived of growth factors, as well as in brains of (FAD)APP-transgenic mice, ASK1 was upregulated in neuronal projections, where it interacted with APP. In non-transgenic brains, ASK1 and APP associated mainly in the ER. Our results indicate that recruitment of ASK1 to stress-signaling complexes assembled with APP may be triggered and enhanced by cellular stress. Thus, ASK1 may be the apical MAPKKK in a signaling complex assembled with APP as a response to stress.
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PMID:Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex. 1771 30

Kinesin motors drive the intracellular transport of multiple cargoes along microtubule tracks; yet, how kinesins discriminate among their many potential cargoes is unknown. We tested whether Kinesin-1 cargoes compete, co-operate or are transported independently of each other. We focused on Kinesin-1 cargoes that bind directly to the kinesin light chain (KLC) subunit, namely the c-Jun NH(2)-terminal kinase-interacting proteins (JIPs) 1 and 3, Kidins220/ARMS and PAT1. Overexpression of individual cargo proteins in differentiated CAD cells resulted in mislocalization of the endogenous protein but had no effect on localization of other cargo proteins to neurite tips. Thus, while transport of distinct cargoes is saturable, they do not compete with each other. Interestingly, we found that low expression of JIP1 or JIP3 enhanced the transport of the other JIP to neurite tips. Moreover, JIP1 and JIP3 require each other for transport. Co-operative transport is due to an interaction between JIP1 and JIP3 as well as distinct binding sites on the KLC tetratricopeptide repeat (TPR) bundle: the TPR groove binds to C-terminal residues of JIP1, whereas the TPR surface binds to internal residues in JIP3. Formation of a JIP1/JIP3/KLC complex is necessary for efficient JIP1 or JIP3 transport in neuronal cells. Thus, JIP scaffolding proteins are transported in a co-operative manner, despite the independent transport of other Kinesin-1 cargoes.
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PMID:Co-operative versus independent transport of different cargoes by Kinesin-1. 1826 9


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