Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we identified tyrosine-phosphorylated Vav1 as an early point of integration between the signaling routes triggered by the T-cell receptor and CD28 in human T-cell leukemia cells. Costimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. T-cell stimulation induced the recruitment of Vav1 to an inducible multiprotein T-cell activation signaling complex at the plasma membrane. Vav1 activated the mitogen-activated protein kinases JNK and p38. The Vav1-mediated activation of JNK employed a pathway involving Rac, HPK1, MLK3, and MKK7. The costimulation-induced activation of p38 was inhibited by dominant negative forms of Vav1, Rac, and MKK6. Here we show that Vav1 also induces transcription factors that bind to the CD28RE/AP element contained in the interleukin-2 promoter. A detailed mutational analysis of Vav1 revealed a series of constitutively active and nonfunctional forms of Vav1. Almost all inactive versions were mutated in their Dbl homology domain and behaved as dominant negative mutants that impaired costimulation-induced activation of JNK, p38, and CD28RE/AP-dependent transcription. In contrast to NF-AT-dependent transcription, Vav1-mediated transcriptional induction of the CD28RE/AP element in the interleukin-2 promoter could only partially be inhibited by cyclosporin A, suggesting a dual role of Vav1 for controlling Ca(2+)-dependent and -independent events.
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PMID:Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription. 1084 38

Ral GTPase activity is a crucial cell-autonomous factor supporting tumor initiation and progression. To decipher pathways impacted by Ral, we have generated null and hypomorph alleles of the Drosophila melanogaster Ral gene. Ral null animals were not viable. Reduced Ral expression in cells of the sensory organ lineage had no effect on cell division but led to postmitotic cell-specific apoptosis. Genetic epistasis and immunofluorescence in differentiating sensory organs suggested that Ral activity suppresses c-Jun N-terminal kinase (JNK) activation and induces p38 mitogen-activated protein (MAP) kinase activation. HPK1/GCK-like kinase (HGK), a MAP kinase kinase kinase kinase that can drive JNK activation, was found as an exocyst-associated protein in vivo. The exocyst is a Ral effector, and the epistasis between mutants of Ral and of msn, the fly ortholog of HGK, suggest the functional relevance of an exocyst/HGK interaction. Genetic analysis also showed that the exocyst is required for the execution of Ral function in apoptosis. We conclude that in Drosophila Ral counters apoptotic programs to support cell fate determination by acting as a negative regulator of JNK activity and a positive activator of p38 MAP kinase. We propose that the exocyst complex is Ral executioner in the JNK pathway and that a cascade from Ral to the exocyst to HGK would be a molecular basis of Ral action on JNK.
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PMID:The Ral/exocyst effector complex counters c-Jun N-terminal kinase-dependent apoptosis in Drosophila melanogaster. 1700 Jul 65