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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The structure of protein kinase C zeta (PKC zeta) is unusual with respect to other PKCs, as it lacks the C2 domain and possesses only one zinc finger region. Consequently, PKC zeta can not be activated by diacylglycerol or phorbol esters and is not downregulated by prolonged treatment by phorbol esters nor blocked by commonly utilized PKC inhibitors. In this study, we have explored the idea that PKC zeta might participate in proliferative pathways. Our findings show that marked overexpression of mammalian PKC zeta does not alter the growth characteristics of NIH 3T3 cells, nor induces cellular transformation. Furthermore, mammalian PKC zeta does not potentiate the transforming ability of oncogenes such as ras, sis and the muscarinic receptor m1. In this context, PKC zeta or its dominant negative mutant do not affect MAP kinase activation by oncogenes or growth factors. Taken together, our findings demonstrate that mammalian PKC zeta does not directly participate in signaling pathways involved in oncogenic transformation.
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PMID:Overexpression of mammalian protein kinase C-zeta does not affect the growth characteristics of NIH 3T3 cells. 763 44

GATA-2 is a member of a family of transcription factors which bind a common DNA sequence motif (WGA-TAR) through an evolutionarily conserved zinc finger domain. An essential role for GATA-2 in the development of hematopoietic stem cells has recently been shown in gene targeting experiments in mice. Here we show that GATA-2 exists in hematopoietic progenitor cells as a phosphoprotein. Stimulation of progenitors with interleukin-3 (IL-3) results in enhanced phosphorylation of GATA-2 which occurs within 5 min. IL-3 is known to signal in part through mitogen-activated protein (MAP) kinase, and evidence for MAP kinase signaling in the control of GATA-2 phosphorylation was obtained by genetically manipulating the MAP kinase pathway in COS cells using either constitutively activating or interfering mutants of MAP kinase kinase. Furthermore, using an interfering mutant of MAP kinase kinase, we directly demonstrated a critical role for the MAP kinase pathway in the IL-3-dependent phosphorylation of GATA-2 in hematopoietic progenitor cells. Finally, in vitro phosphorylation experiments using recombinant GATA-2 raise the possibility that MAP kinase itself may phosphorylate GATA-2. Our results provide evidence for phosphorylation via the MAP kinase pathway constituting a cytoplasmic link between GATA-2 and growth factor receptors and are consistent with the hypothesis that GATA-2 is involved in the growth factor responsiveness and proliferation control of hematopoietic progenitor cells.
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PMID:Regulation of GATA-2 phosphorylation by mitogen-activated protein kinase and interleukin-3. 787 60

Ash1 (for asymmetric synthesis of HO) was first uncovered in genetic screens that revealed its role in mating-type switching. Ash1 prevents HO expression in daughter cells. Because Ash1 has a zinc finger-like domain related to that of the GATA family of transcription factors, it presumably acts by repressing HO transcription. Nonswitching diploid cells also express Ash1, suggesting it could have functions in addition to regulation of HO expression. We show here that Ash1 has an essential function for pseudohyphal growth. Our epistasis analyses are consistent with the deduction that Ash1 acts separately from the mitogen-activated protein kinase cascade and Ste12. Similarly to the case in yeast form cells, Ash1 is asymmetrically localized to the nuclei of daughter cells during pseudohyphal growth. This asymmetric localization reveals that there is a previously unsuspected daughter cell-specific function necessary for pseudohyphal growth.
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PMID:Ash1, a daughter cell-specific protein, is required for pseudohyphal growth of Saccharomyces cerevisiae. 956 7

The subcellular localization of the TNF receptor-associated factor-2 (TRAF2) adaptor protein in human endothelial cells, which mediates proinflammatory responses of TNF, has been analyzed by confocal immunofluorescence microscopy and by Western blotting of fractionated cell extracts. Rabbit antisera reactive with either amino- or carboxyl-terminal TRAF2 peptides frequently but not uniformly stain nuclei of cultured HUVEC or the established human endothelial cell line, ECV304. However, Western blotting reveals significant heterogeneity in the reactivities of these polyclonal Abs. Transiently transfected HUVEC expressing FLAG epitope-tagged TRAF2 consistently show prominent nuclear localization, and deletion mutants of TRAF2 identify the portion of the molecule responsible for nuclear localization as the amino-terminal ring finger domain. TNF treatment does not appear to influence the localization of endogenous or transfected TRAF2 protein. Transfection of the amino-terminal half of the TRAF2 molecule, containing the ring and zinc finger domains, which localizes to the nucleus, results in activation of E-selectin but not of NF-kappaB promoter-reporter gene transcription or of c-Jun N-terminal kinase activation. These observations suggest that TRAF2 may reside in the nucleus and directly regulate transcription, independent of its role in cytoplasmic signal transduction.
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PMID:The N-terminal domains target TNF receptor-associated factor-2 to the nucleus and display transcriptional regulatory activity. 964 39

The bcl-6 proto-oncogene encodes a POZ/zinc finger transcriptional repressor expressed in germinal center (GC) B and T cells and required for GC formation and antibody affinity maturation. Deregulation of bcl-6 expression by chromosomal rearrangements and point mutations of the bcl-6 promoter region are implicated in the pathogenesis of B-cell lymphoma. The signals regulating bcl-6 expression are not known. Here we show that antigen receptor activation leads to BCL-6 phosphorylation by mitogen-activated protein kinase (MAPK). Phosphorylation, in turn, targets BCL-6 for rapid degradation by the ubiquitin/proteasome pathway. These findings indicate that BCL-6 expression is directly controlled by the antigen receptor via MAPK activation. This signaling pathway may be crucial for the control of B-cell differentiation and antibody response and has implications for the regulation of other POZ/zinc finger transcription factors in other tissues.
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PMID:Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. 964

The diverse biological effects of the tumor necrosis factor (TNF) receptor superfamily are believed to be mediated in part through TNF receptor-associated factors (TRAFs), a family of cytoplasmic adaptor proteins which can activate intracellular signaling pathways, including the nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) pathways. TRAFs 2, 5, and 6 strongly activate both pathways when overexpressed; however, TRAF 3 (a close homologue of TRAF 5) does not significantly activate either pathway. The current study addresses the structural basis for this difference by substituting corresponding domains of TRAF 5 into TRAF 3 and testing activation of both pathways. A small region of TRAF 5 (the first zinc finger and 10 residues of the second zinc finger) is sufficient to convert TRAF 3 into an activator of both pathways. Also, an intact zinc ring finger is required for NF-kappaB activation but not JNK activation. In agreement with this finding, TRAF 2A, a TRAF 2 splice variant with an altered ring finger, is a specific activator of JNK. These findings suggest that different domains of TRAFs may be involved in NF-kappaB and JNK signaling. Also, alternative splicing of TRAFs may represent a novel mechanism whereby TNF family receptors can mediate distinct downstream effects in different tissues.
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PMID:An intact zinc ring finger is required for tumor necrosis factor receptor-associated factor-mediated nuclear factor-kappaB activation but is dispensable for c-Jun N-terminal kinase signaling. 973 79

Many members of the tumor necrosis factor (TNF) receptor superfamily and the interleukin-1 (IL-1) receptor engage intracellular signaling pathways including the nuclear factor kappaB (NF-kappaB)-, c-jun N-terminal kinase (JNK)-, and extracellular signal-regulated kinase (ERK) pathways by direct or indirect interaction with TNF receptor-associated factor (TRAF) molecules. To date, six mammalian members of the TRAF family have been identified. Searching public databases with a sequence pattern comprising 19 conserved amino acid residues derived from the carboxyl-terminal part of the TRAF homology domain, we found significant sequence homologies to a stretch of genomic DNA from Caenorhabditis elegans which encodes 1 of 12 exons of a putative protein. The sequence of this putative protein shows up to 29% sequence identity to the mammalian TRAFs and is therefore designated C. elegans TRAF (CeTRAF). The CeTRAF molecule has an amino-terminal RING finger motif followed by four zinc finger structures and a carboxyl-terminal TRAF domain, a composition which is also found in most of the mammalian TRAFs. Reverse transcription-PCR and sequencing analysis of the respective amplicon clearly demonstrates that CeTRAF is in fact transcribed in C. elegans. The existence of a member of the TRAF family in C. elegans provides strong evidence for evolutionary conserved pathways linking cell surface receptors to activation of JNK, ERK, and NF-kappaB.
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PMID:Identification of a TRAF (TNF receptor-associated factor) gene in Caenorhabditis elegans. 984 6

The protein kinase KSR-1 is a recently identified participant in the Ras signaling pathway. The subcellular localization of KSR-1 is variable. In serum-deprived cultured cells, KSR-1 is primarily found in the cytoplasm; in serum-stimulated cells, a significant portion of KSR-1 is found at the plasma membrane. To identify the mechanism that mediates KSR-1 translocation, we performed a yeast two-hybrid screen. Three clones that interacted with KSR-1 were found to encode the full-length gamma10 subunit of heterotrimeric G-proteins. KSR-1 also interacted with gamma2 and gamma3 in a two-hybrid assay. Deletion analysis demonstrated that the isolated CA3 domain of KSR-1, which contains a cysteine-rich zinc finger-like domain, interacted with gamma subunits. Coimmunoprecipitation experiments demonstrated that KSR-1 bound to beta1 gamma3 subunits when all three were transfected into cultured cells. Lysophosphatidic acid treatment of cells induced KSR-1 translocation to the plasma membrane from the cytoplasm that was blocked by administration of pertussis toxin but not by dominant-negative Ras. Finally, transfection of wild-type KSR-1 inhibited beta1 gamma3-induced mitogen-activated protein kinase activation in cultured cells. These results demonstrate that KSR-1 translocation to the plasma membrane is mediated, at least in part, by an interaction with beta gamma and that this interaction may modulate mitogen-activated protein kinase signaling.
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PMID:KSR-1 binds to G-protein betagamma subunits and inhibits beta gamma-induced mitogen-activated protein kinase activation. 1007 96

We have cloned a new human gene, cbl-3, which encodes a protein with marked homology to the cbl family of proteins. The predicted protein encoded by this gene retains the conserved phosphotyrosine binding domain (PTB) in the N-terminal and the zinc finger but is significantly shorter (MW 52.5 kDa) than the other mammalian cbl proteins. The protein lacks the extensive proline rich domain and leucine zipper seen in c-cbl and cbl-b and structurally most resembles the C. elegans and Drosophila cbl proteins. The gene is ubiquitously expressed with highest expression in the aerodigestive tract, prostate, adrenal gland, and salivary gland. The protein is phosphorylated and recruited to the EGFR upon EGF stimulation and inhibits EGF stimulated MAP kinase activation. In comparison to the other mammalian cbl proteins (e.g. cbl-b), cbl-3 interacts with a restricted range of proteins containing Src Homology 3 regions. An alternatively spliced form of the cbl-3 protein was also identified which deletes a critical region of the PTB domain and which does not interact with the EGFR nor inhibit EGF stimulated MAP kinase activation. These data demonstrate that cbl-3, a novel mammalian cbl protein, is a regulator of EGFR mediated signal transduction.
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PMID:cbl-3: a new mammalian cbl family protein. 1036 57

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an intracellular protein involved in signal transduction from TNF receptor I and II and related receptors. TRAF2 is required for TNF-induced activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and TRAF2 can also mediate activation of NF-kappaB. Here we have identified the actin-binding protein Filamin (actin-binding protein-280) as a TRAF2-interacting protein. Filamin binds to the Ring zinc finger domain of TRAF2. Overexpressed Filamin inhibits TRAF2-induced activation of JNK/SAPK and of NF-kappaB. Furthermore, ectopically expressed Filamin inhibits NF-kappaB activation induced via TNF, interleukin-1, Toll receptors, and TRAF6 but not activation induced via overexpression of NIK, a downstream effector in these pathways. Importantly, TNF fails to activate SAPK or NF-kappaB in a human melanoma cell line deficient in Filamin. Reintroduction of Filamin into these cells restores the TNF response. The data imply a role for Filamin in inflammatory signal transduction pathways.
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PMID:Physical and functional interaction of filamin (actin-binding protein-280) and tumor necrosis factor receptor-associated factor 2. 1061 15


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