Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.25 (MEKK1)
1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified a developmentally regulated, putative MEK kinase (MEKKalpha) that contains an F-box and WD40 repeats and plays a complex role in regulating cell-type differentiation and spatial patterning. Cells deficient in MEKKalpha develop precociously and exhibit abnormal cell-type patterning with an increase in one of the prestalk compartments (pstO), a concomitant reduction in the prespore domain, and a loss of the sharp compartment boundaries, resulting in overlapping prestalk and prespore domains. Overexpression of MEKKalpha or MEKKalpha lacking the WD40 repeats results in very delayed development and a severe loss of compartment boundaries. Prespore and prestalk cells are interspersed throughout the slug. Analysis of chimeric organisms suggests that MEKKalpha function is required for the proper induction and maintenance of prespore cell differentiation. We show that the WD40 repeats target MEKKalpha to the cortical region of the cell, whereas the F-box/WD40 repeats direct ubiquitin-mediated MEKKalpha degradation. We identify a UBC and a UBP (ubiquitin hydrolase) that interact with the F-box/WD40 repeats. Our findings indicate that cells lacking the ubiquitin hydrolase have phenotypes similar to those of MEKKalpha null (mekkalpha-) cells, further supporting a direct genetic and biochemical interaction between MEKKalpha, the UBC, and the UBP. We demonstrate that UBC and UBP differentially control MEKKalpha ubiquitination/deubiquitination and degradation through the F-box/WD40 repeats in a cell-type-specific and temporally regulated manner. Our results represent a novel mechanism that includes targeted protein degradation by which MAP kinase cascade components can be controlled. More importantly, our findings suggest a new paradigm of spatial and temporal control of the kinase activity controlling spatial patterning during multicellular development, which parallels the temporally regulated degradation of proteins required for cell-cycle progression.
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PMID:A novel, putative MEK kinase controls developmental timing and spatial patterning in Dictyostelium and is regulated by ubiquitin-mediated protein degradation. 983 8

Recent evidence indicates that nuclear factor-kappaB (NF-kappaB), a transcription factor critically important for immune and inflammatory responses, is activated by a protein kinase cascade. The essential features of this cascade are that a mitogen-activated protein kinase kinase kinase (MAP3K) activates an IkappaB kinase (IKK) that site-specifically phosphorylates IkappaB. The IkappaB protein, which ordinarily sequesters NF-kappaB in the cytoplasm, is subsequently degraded by the ubiquitin-proteasome pathway, thereby allowing the nuclear translocation of NF-kappaB. Thus far, only two MAP3Ks, NIK and MEKK1, have been identified that can activate this pathway. We now show that MEKK2 and MEKK3 can in vivo activate IKK-alpha and IKK-beta, induce site-specific IkappaBalpha phosphorylation, and, relatively modestly, activate an NF-kappaB reporter gene. In addition, dominant negative versions of either IKK-alpha or IKK-beta abolish NF-kappaB activation induced by MEKK2 or MEKK3, thereby providing evidence that these IKKs mediate the NF-kappaB-inducing activities of these MEKKs. In contrast, other MAP3Ks, including MEKK4, ASK1, and MLK3, fail to show evidence of activation of the NF-kappaB pathway. We conclude that a distinct subset of MAP3Ks can activate NF-kappaB.
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PMID:Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. 1008 62

ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Moreover, both MEKK1 kinase activity and the docking motif on ERK1/2 were involved in ERK1/2 ubiquitination. Significantly, cells expressing ERK2 with the docking motif mutation were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity.
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PMID:The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. 1204 32

Although Jun amino-terminal kinase (JNK) is known to mediate a physiological stress signal that leads to cell death, the exact role of the JNK pathway in the mechanisms underlying intrinsic cell death is largely unknown. Here we show through a genetic screen that a mutant of Drosophila melanogaster tumour-necrosis factor receptor-associated factor 1 (DTRAF1) is a dominant suppressor of Reaper-induced cell death. We show that Reaper modulates the JNK pathway through Drosophila inhibitor-of-apoptosis protein 1 (DIAP1), which negatively regulates DTRAF1 by proteasome-mediated degradation. Reduction of JNK signals rescues the Reaper-induced small eye phenotype, and overexpression of DTRAF1 activates the Drosophila ASK1 (apoptosis signal-regulating kinase 1; a mitogen-activated protein kinase kinase kinase) and JNK pathway, thereby inducing cell death. Overexpresson of DIAP1 facilitates degradation of DTRAF1 in a ubiquitin-dependent manner and simultaneously inhibits activation of JNK. Expression of Reaper leads to a loss of DIAP1 inhibition of DTRAF1-mediated JNK activation in Drosophila cells. Taken together, our results indicate that DIAP1 may modulate cell death by regulating JNK activation through a ubiquitin#150;proteasome pathway.
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PMID:Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila. 1219 95

Axin is a multifunctional protein, regulating Wnt signaling and the c-Jun N-terminal/stress-activated protein kinase (JNK/SAPK) pathway as well as tumorigenesis. In the present study, we found that Axin interacts with three SUMO-1 (small ubiquitin-related modifier) conjugating enzymes 3 (E3), PIAS1, PIASxbeta, and PIASy. The extreme C-terminal six amino acid residues of Axin are critical for the Axin/E3 interaction as deletion of the six residues (AxinDeltaC6) completely abolished the ability of Axin to interact with E3 enzymes. AxinDeltaC6 also failed to activate JNK, although it was intact in both its interaction with MEKK1 and homodimerization. Consistent with the presence of a doublet of the KV(E/D) sumoylation consensus motif at the C-terminal end (KVEKVD), we found that Axin is heavily sumoylated. Deletion of the C-terminal six amino acids drastically reduced sumoylation, indicating that the C-terminal six amino acids stretch is the main sumoylation site for Axin. Sumoylation-defective mutants failed to activate JNK but effectively destabilized beta-catenin and attenuated LEF1 transcriptional activity. In addition, we show that dominant negative Axin mutants blocked PIAS-mediated JNK activation, in accordance with the requirement of sumoylation for Axin-mediated JNK activation. Taken together, we demonstrate that sumoylation plays a role for Axin to function in the JNK pathway.
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PMID:SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling. 1222 91

PHD domains constitute a widely distributed subfamily of zinc fingers whose biochemical functions have been unclear until now. Recently, several PHD-containing viral proteins have been identified that promote immune evasion by downregulating proteins that govern immune recognition. Studies show that these viral regulators lead to ubiquitination of their targets by functioning as E3 ubiquitin ligases -- an activity that requires the PHD motif. These are the first examples linking the PHD domain to E3 activity, but the recent discovery of PHD-dependent E3 activity in the cellular kinase MEKK1 and the close structural relation of PHD domains to RING fingers hint that many other PHD proteins might share this activity.
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PMID:PHD domains and E3 ubiquitin ligases: viruses make the connection. 1279 Dec 92

The proteasome is a multisubunit proteolytic enzyme comprising activator complexes bound to the 20 S catalytic core. The functions of the proteasomal activator (PA) 700 in ubiquitin/ATP-dependent protein degradation and of the PA28 alpha/beta activators in antigen presentation are well defined. However, the function of a third PA, PA28 gamma, remains elusive. We now show that mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase kinase 3 (MEKK3), a MAPK kinase kinase (MAPKKK) involved in MAPK kinase 7 (MKK7)-c-Jun N-terminal kinase ('JNK') and MKK6-p38 signalling, can bind PA28 gamma but not PA28 alpha. In contrast, B-Raf, a MAPKKK specific for the MAPK/ERK kinase ('MEK')-ERK module, binds PA28 gamma and alpha. The PA28 gamma-binding domain of MEKK3 is located within its N-terminal regulatory domain (amino acids 1-178). Expression of MEKK3 in Cos-7 cells led to an increase in endogenous and co-expressed PA28 gamma protein levels, whereas kinase-deficient MEKK3 had no effect on PA28 gamma expression. Furthermore, in vitro assays indicated that PA28 gamma was a MEKK3 substrate. MEKK3 represents the first protein kinase capable of binding and phosphorylating a PA, and provides a potential mechanism to link stress-activated protein kinase signalling with the PA28 gamma-dependent proteasome.
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PMID:MEKK3 interacts with the PA28 gamma regulatory subunit of the proteasome. 1265 Jun 40

Recently, it has been reported that PHD fingers of MEKK1 kinase and a family of viral and cellular membrane proteins have E3 ubiquitin ligase activity. Here we describe unique sequence and structural signatures that distinguish PHD fingers from RING fingers, which function primarily as E3 ubiquitin ligases, and demonstrate that the Zn-binding modules of the above proteins are distinct versions of the RING domain rather than PHD fingers. Thus, currently available data reveal extreme versatility of RINGs and their derivatives that function as E3 ubiquitin ligases but provide no evidence of this activity among PHD fingers whose principal function appears to involve specific protein-protein and possibly protein-DNA interactions in chromatin.
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PMID:Scores of RINGS but no PHDs in ubiquitin signaling. 1269 63

TAK1 mitogen-activated protein kinase kinase kinase participates in the Interleukin-1 (IL-1) signaling pathway by mediating activation of JNK, p38, and NF-kappaB. TAK1-binding protein 2 (TAB2) was previously identified as an adaptor that links TAK1 to an upstream signaling intermediate, tumor necrosis factor receptor-associated factor 6 (TRAF6). Recently, ubiquitination of TRAF6 was shown to play an essential role in the activation of TAK1. However, the mechanism by which IL-1 induces TRAF6 ubiquitination remains to be elucidated. Here we report that TAB2 functions to facilitate TRAF6 ubiquitination and thereby mediates IL-1-induced cellular events. A conserved ubiquitin binding domain in TAB2, the CUE domain, is important for this function. We also found that TAB2 promotes the assembly of TRAF6 with a downstream kinase, IkappaB kinase (IKK). These results show that TAB2 acts as a multifunctional signaling molecule, facilitating both IL-1-dependent TRAF6 ubiquitination and assembly of the IL-1 signaling complex.
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PMID:TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway. 1583 73

Infection of Drosophila by Gram-negative bacteria triggers a signal transduction pathway (the IMD pathway) culminating in the expression of genes encoding antimicrobial peptides. A key component in this pathway is a Drosophila IkappaB kinase (DmIKK) complex, which stimulates the cleavage and activation of the NF-kappaB transcription factor Relish. Activation of the DmIKK complex requires the MAP3K dTAK1, but the mechanism of dTAK1 activation is not understood. In human cells, the activation of TAK1 and IKK requires the human ubiquitin-conjugating enzymes Ubc13 and UEV1a. Here we demonstrate that the Drosophila homologs of Ubc13 and UEV1a are similarly required for the activation of dTAK1 and the DmIKK complex. Surprisingly, we find that the Drosophila caspase DREDD and its partner dFADD are required for the activation of DmIKK and JNK, in addition to their role in Relish cleavage. These studies reveal an evolutionarily conserved role of ubiquitination in IKK activation, and provide new insights into the hierarchy of signaling components in the Drosophila antibacterial immunity pathway.
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PMID:The role of ubiquitination in Drosophila innate immunity. 1608 24


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