Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deltex is known as a Notch signal mediator, but its physiological action mechanism is poorly understood. Here we identified a new regulatory role of Deltex in T-cell activation. Deltex expression was constitutive in resting T cells and was reduced upon T-cell receptor (TCR)-stimulated activation. The biological role of Deltex is supported by the enhanced T-cell activation when Deltex1 was down-regulated by small interfering RNA. Overexpression of Deltex1 suppressed T-cell activation but not the proximal TCR activation events. The impaired activation of mitogen-activated protein kinase by Deltex could be partly attributed to a selective down-regulation of MEKK1 protein in T cells. We further found that Deltex promoted degradation of the C-terminal catalytic fragment of MEKK1 [MEKK1(C)]. Deltex1 interacted directly with MEKK1(C) and stimulated the ubiquitination of MEKK1(C) as shown by in vivo and in vitro ubiquitination analysis. Therefore, MEKK1(C), the dominant form of MEKK1 in T cells, is a target of Deltex E3 ubiquitin ligase. Our results reveal a novel mechanism as to how Deltex selectively suppresses T-cell activation through degradation of a key signaling molecule, MEKK1.
 ...
PMID:Deltex regulates T-cell activation by targeted degradation of active MEKK1. 1568 88

Synapses display a stereotyped ultrastructural organization, commonly containing a single electron-dense presynaptic density surrounded by a cluster of synaptic vesicles. The mechanism controlling subsynaptic proportion is not understood. Loss of function in the C. elegans rpm-1 gene, a putative RING finger/E3 ubiquitin ligase, causes disorganized presynaptic cytoarchitecture. RPM-1 is localized to the presynaptic periactive zone. We report that RPM-1 negatively regulates a p38 MAP kinase pathway composed of the dual leucine zipper-bearing MAPKKK DLK-1, the MAPKK MKK-4, and the p38 MAP kinase PMK-3. Inactivation of this pathway suppresses rpm-1 loss of function phenotypes, whereas overexpression or constitutive activation of this pathway causes synaptic defects resembling rpm-1(lf) mutants. DLK-1, like RPM-1, is localized to the periactive zone. DLK-1 protein levels are elevated in rpm-1 mutants. The RPM-1 RING finger can stimulate ubiquitination of DLK-1. Our data reveal a presynaptic role of a previously unknown p38 MAP kinase cascade.
 ...
PMID:Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. 1570 98

Ligand-induced receptor down-regulation by endocytosis is a critical process regulating the intensity and duration of receptor tyrosine kinase signaling. Ubiquitylation of specific receptor tyrosine kinases, for example, the epidermal growth factor receptor (EGFR) by the E3 ubiquitin ligase c-Cbl, provides a sorting signal for lysosomal degradation and leads to termination of receptor signaling. Cortactin, which couples the endocytic machinery to dynamic actin networks, is encoded by EMS1, a gene commonly amplified in breast and head and neck cancers. One mechanism whereby cortactin overexpression contributes to tumor progression is by enhancing tumor cell invasion and metastasis. However, in this study, we show that overexpression of cortactin in HeLa cells markedly inhibits ligand-induced down-regulation of the EGFR. This is independent of alterations in receptor autophosphorylation and correlates with impaired c-Cbl phosphorylation and association with the EGFR, reduced EGFR ubiquitylation, and sustained EGF-induced extracellular signal-regulated kinase activation. Furthermore, analysis of a panel of head and neck squamous cell carcinoma (HNSCC) cell lines revealed that cortactin overexpression is associated with attenuated ligand-induced EGFR down-regulation. Importantly, RNAi-mediated reduction of cortactin expression in an 11q13-amplified HNSCC cell line accelerates EGFR degradation. This represents the first demonstration of modulation of growth factor receptor signaling by cortactin. Moreover, enhanced EGFR signaling due to cortactin overexpression may provide an alternative explanation for EMS1 gene amplification in human cancers.
 ...
PMID:Cortactin overexpression inhibits ligand-induced down-regulation of the epidermal growth factor receptor. 1583 60

Parkin, an E3 ubiquitin ligase, has been found to be responsible for autosomal recessive juvenile parkinsonism characterized primarily by selective loss of dopaminergic neurons with subsequent defects in movements. However, the molecular mechanisms underlying this neuron loss remain elusive. Here, we characterized Drosophila parkin loss-of-function mutants, which exhibit shrinkage of dopaminergic neurons with decreased tyrosine hydroxylase level and impaired locomotion. The behavioral defect of parkin mutant flies was partially restored by administering L-DOPA, and the dopamine level in the brains of parkin mutant flies was highly decreased. Intriguingly, we found that c-Jun N-terminal kinase (JNK) is strongly activated in the dopaminergic neurons of parkin mutants and that impaired dopaminergic neuron phenotypes are dependent on the activation of the JNK signaling pathway. In consistent with this, our epistatic analysis and mammalian cell studies showed that Parkin inhibits the JNK signaling pathway in an E3 activity-dependent manner. These results suggest that loss of Parkin function up-regulates the JNK signaling pathway, which may contribute to the vulnerability of dopaminergic neurons in Drosophila parkin mutants and perhaps autosomal recessive juvenile parkinsonism patients.
 ...
PMID:Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. 1600 72

POSH (plenty of SH3s) acts as a scaffold that links activated Rac1 and downstream c-Jun N-terminal kinase (JNK) signaling modules. However, it is unknown whether it's functional domain-mediated roles including the interesting RING-finger domain or its cellular function. Here, we provide evidence that subcellular localization of POSH is regulated by a particular domain of the protein and POSH was colocalized with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) on early endosomes via interaction of Hrs with POSH's two rear SH3 domains. Moreover, the RING domain of POSH specifically regulates the stability of Hrs, but not of JNK1, via a ubiquitin-proteasomal degradation pathway. Finally, we demonstrate that JNK1 does not interact with Hrs under the conditions of POSH interacted with Hrs, but instead reduces the POSH-catalyzed ubiquitination of Hrs and their reciprocal interaction. Together, these data suggest that POSH has a distinct role as a specific E3 ubiquitin ligase for Hrs on early endosomes, and there exists a relationship between its separate activities as a scaffold and as an E3.
 ...
PMID:Novel function of POSH, a JNK scaffold, as an E3 ubiquitin ligase for the Hrs stability on early endosomes. 1608 64

POSH (Plenty of SH3s) has distinct roles as a scaffold for specific c-Jun N-terminal kinase (JNK) signaling modules and as an E3 ubiquitin ligase. The physiological function of POSH remains unclear, however, and its possible involvement in developmental processes motivated the present study wherein the Xenopus orthologue of POSH (xPOSH) was examined for its potential role during Xenopus early embryogenesis. Loss-of-function analysis using morpholino oligonucleotides demonstrated that POSH was essential for Xenopus anterior neural development, although not Spemann organizer formation and early neurogenesis, through the formation of an active JNK signaling complex. Moreover, POSH-mediated JNK pathway was essential for apoptosis in anterior neural tissues. Finally, the present findings demonstrate that RING (Really Interesting New Gene) domain-mediated E3 ubiquitin ligase activity of POSH was not involved in POSH-mediated JNK pathway in vivo. Together, these data suggest that the active JNK signaling complex formed of POSH and the JNK module is essential for the expression of anterior neural genes and apoptosis in Xenopus anterior development.
 ...
PMID:The assembly of POSH-JNK regulates Xenopus anterior neural development. 1612 90

The immune system is capable of mounting robust responses against invading pathogens but refrains from attacking self. Many studies have focused on tolerance induction of Th1 cells, whose failure results in development of autoimmune diseases. However, the molecular mechanisms governing tolerance induction in Th2 cells and its relation to allergic responses remain unclear. Here we used both in vivo and in vitro protocols to demonstrate that Th2 cells either containing a mitogen and extracellular kinase kinase 1 (MEKK1) mutant or lacking JNK1 or the E3 ubiquitin ligase Itch cannot be tolerized. In a mouse allergic model, injection of high-dose tolerizing antigen failed to block the development of airway inflammation in Itch-/- mice. This study suggests that MEKK1-JNK signaling regulates Itch E3 ligase-mediated tolerogenic process in Th2 cells. These findings have therapeutic implications for allergic diseases.
 ...
PMID:Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. 1655 1

The proto-oncogenic protein c-Cbl was discovered as the cellular form of v-Cbl, a retroviral transforming protein. This was followed over the years by important discoveries, which identified c-Cbl and other Cbl-family proteins as key players in several signaling pathways. c-Cbl has donned the role of a multivalent adaptor protein, capable of interacting with a plethora of proteins, and has been shown to positively influence certain biological processes. The identity of c-Cbl as an E3 ubiquitin ligase unveiled the existence of an important negative regulatory pathway involved in maintaining homeostasis in protein tyrosine kinase (PTK) signaling. Recent years have also seen the emergence of novel regulators of Cbl, which have provided further insights into the complexity of Cbl-influenced pathways. This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects. The major sections of the review are as follows: Structure and genomic organization of Cbl proteins; Phosphorylation of Cbl; Interactions of Cbl; Localization of Cbl; Mechanism of effects of Cbl: (a) Ubiquitylation-dependent events: This section elucidates the mechanism of Cbl-mediated downregulation of EGFR and details the PTK and non-PTKs targeted by Cbl. In addition, it addresses the functional requirements for E3 Ubiquitin ligase activity of Cbl and negative regulation of Cbl-mediated downregulation of PTKs, (b) Adaptor functions: This section discusses the mechanisms of adaptor functions of Cbl in mitogen-activated protein kinase (MAPK) activation, insulin signaling, regulation of Ras-related protein 1 (Rap1), PI-3' kinase signaling, and regulation of Rho-family GTPases and cytoskeleton; Biological functions: This section gives an account of the diverse biological functions of Cbl and includes the role of Cbl in transformation, T-cell signaling and thymus development, B-cell signaling, mast-cell degranulation, macrophage functions, bone development, neurite growth, platelet activation, muscle degeneration, and bacterial invasion; Conclusions and perspectives.
 ...
PMID:The Cbl family proteins: ring leaders in regulation of cell signaling. 1674 4

The E3 ubiquitin ligase IMP (impedes mitogenic signal propagation) was isolated as a novel Ras effector that negatively regulates ERK1/2 activation. Current evidence suggests that IMP limits the functional assembly of Raf/MEK complexes by inactivation of the KSR1 adaptor/scaffold protein. Interaction with Ras-GTP stimulates IMP autoubiquitination to relieve limitations on KSR function. The elevated sensitivity of IMP-depleted cells to ERK1/2 pathway activation suggests IMP acts as a signal threshold regulator by imposing reversible restrictions on the assembly of functional Raf/MEK/ERK kinase modules. These observations challenge commonly held concepts of signal transmission by Ras to the MAPK pathway and provide evidence for the role of amplitude modulation in tuning cellular responses to ERK1/2 pathway engagement. Here we describe details of the methods, including RNA interference, ubiquitin ligase assays, and protein complex analysis, that can be used to display the Ras-sensitive contribution of IMP to KSR-dependent modulation of the Raf/MEK/ERK pathway.
 ...
PMID:Ras-sensitive IMP modulation of the Raf/MEK/ERK cascade through KSR1. 1675 28

Sprouty was first discovered through its downregulatory effect on fibroblast growth factor (FGF) receptor pathway during tracheal development. Sprouty expression is also induced by the epidermal growth factor receptor (EGFR) cascade in some tissues, including the follicle cells of the ovary, the wing, and eye imaginal disc, and acts to abolish mitogen-activated protein (MAP) kinase activated by EGFR signaling. Sprouty is an intracellular protein that translocates to membrane ruffles upon EGF stimulation by virtue of a translocatory domain within its highly conserved cysteine-rich C-terminal region. Human Sprouty2 (hSpry2) binds the catalytic RING Finger of Casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase that has been identified to target EGFR degradation. Overexpressed hSpry2 induces a prolonged EGFR-mediated MAP kinase activation. hSpry2 acts to sequester c-Cbl molecules from activated EGFR and impedes EGFR ubiquitination and downregulation, thereby potentiating the amplitude and longevity of intracellular signals. The strategies described herein encompass various methods that have been used to measure the status of EGFR following ectopic expression of hSpry2.
 ...
PMID:Regulator of epidermal growth factor signaling: Sprouty. 1678 Feb 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>