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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)

Fission yeast strains auxotrophic for leucine are unable to proliferate in normally supplemented minimal media adjusted to pH 6. 4 or above. High-pH sensitivity can be suppressed by the loss of Pub1, an E3 ubiquitin ligase, or by the replacement of NH(4)(+) with a non-repressing source of nitrogen such as L-proline. In this report we show pub1 to be required for the rapid down-regulation of leucine uptake observed in response to the addition of NH(4)(+) to the growth media. Furthermore, we corroborate earlier results demonstrating the transport of leucine to be negatively influenced by high extracellular pH. pub1 is homologous to the budding yeast nitrogen permease inactivator, NPI1/RSP5, which mediates the ubiquitination and subsequent destruction of NH(4)(+)-sensitive permeases. The high-pH sensitivity of cells auxotrophic for leucine thus seems to reflect an inability of NH(4)(+)-insensitive permeases to transport sufficient leucine under conditions where the proton gradient driving nutrient transport is low, and NH(4)(+)-sensitive permeases have been destroyed. Intriguingly, the partial suppression of both high pH sensitivity, and the inactivating effect of NH(4)(+) on leucine transport, seen in pub1-1 point mutants, becomes as complete as seen in pub1Delta backgrounds when cells have concomitantly lost the function of the spc1 stress-activated MAPK.
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PMID:The pub1 E3 ubiquitin ligase negatively regulates leucine uptake in response to NH(4)(+) in fission yeast. 1046 3

Juvenile salmon migrating from freshwater to the marine environment confront a marked change in environmental osmolality. Using differential display of mRNA expression, we cloned a 1.9-kb cDNA upregulated in isolated tissues of salmon exposed to the hyperosmotic stress associated with transition to the dehydrating marine environment. The cDNA codes for a 21-kDa protein, salmon hyperosmotic protein 21 (Shop21), with 98% identity to Rbx1, an E3 ubiquitin ligase; the protein also contains a novel 81-amino acid domain at the NH(2) terminus not found in Rbx1. Moderate hyperosmotic stress (24 h at 550 mosmol/kg) increased Shop21 transcript 10-fold in branchial lamellae, whereas no upregulation was observed under more severe stress (> or = 800 mosmol/kg). Expression of the gene also was observed in heart and kidney. Replacement of NaCl with mannitol, but not glycerol, also elicited an increase in Shop21 mRNA. Inhibition of the mitogen-activated protein kinase and mitogen-activated extracellular regulated kinase kinase signal transduction pathways failed to blunt the Shop21 response during hyperosmotic stress. Shop21 mRNA also accumulated during thermal stress but to a lesser extent than heat shock protein 70 mRNA. The potential importance of Shop21 to the living animal is suggested by marked upregulation of the gene in salmon after transfer to seawater. The results of these investigations suggest that Shop21 may have a role in targeting selected proteins (e.g., in freshwater ionocytes) nonessential for adaptation to seawater for removal via the proteasome pathway.
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PMID:A homolog of the E3 ubiquitin ligase Rbx1 is induced during hyperosmotic stress of salmon. 1201 Jul 46

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

In vertebrate unfertilized eggs, metaphase arrest in Meiosis II is mediated by an activity known as cytostatic factor (CSF). CSF arrest is dependent upon Mos-dependent activation of the MAPK/Rsk pathway, and Rsk activates the spindle checkpoint kinase Bub1, leading to inhibition of the anaphase-promoting complex (APC), an E3 ubiquitin ligase required for the metaphase/anaphase transition. However, it is not known whether Bub1 is required for the establishment of CSF arrest or whether other pathways also contribute. Here, we show that immunodepletion of Bub1 from egg extracts blocks the ability of Mos to establish CSF arrest, and arrest can be restored by the addition of wild-type, but not kinase-dead, Bub1. The appearance of CSF arrest at Meiosis II may result from coexpression of cyclin E/Cdk2 with the MAPK/Bub1 pathway. Cyclin E/Cdk2 was able to cause metaphase arrest in egg extracts even in the absence of Mos and could also inhibit cyclin B degradation in oocytes when expressed at anaphase of Meiosis I. Once it has been established, metaphase arrest can be maintained in the absence of MAPK, Bub1, or cyclin E/Cdk2 activity. Both pathways are independent of each other, but each appears to block activation of the APC, which is required for cyclin B degradation and the metaphase/anaphase transition.
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PMID:The spindle checkpoint kinase bub1 and cyclin e/cdk2 both contribute to the establishment of meiotic metaphase arrest by cytostatic factor. 1212 78

Since the discovery of the prototypical Sprouty (Spry) protein in Drosophila, there has been an effort to determine how these novel modulators of the Ras/MAP-kinase pathway function. A clue to their mechanism of action comes from the several highly conserved sequences within all the currently known Spry isoforms: an approximately 110-residue cysteine-rich sequence in the C-terminal half that directs Spry proteins to a concentration of signaling proteins at the plasma membrane; a small motif surrounding a tyrosine residue (Y55 in human Spry2) that is responsible for interaction with other proteins. In cultured mammalian cells, hSpry2 inhibits epidermal growth factor receptor (EGFR) endocytosis and subsequently sustains the activation of MAP kinase but negatively regulates the same pathway following stimulation of fibroblast growth factor receptors (FGFRs). Current evidence indicates that Cbl is a key protein that interacts directly with Spry2 following activation of receptor tyrosine kinases (RTKs). It appears to be the ability of Cbl to interact as an E3 ubiquitin ligase on specific target proteins and as a docking protein in other contexts that dictates the differential effects Spry2 has on the Ras/MAP-kinase pathway following EGFR and FGFR activation.
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PMID:Sprouty: how does the branch manager work? 1282 36

In addition to its well described function as an enzymatic inhibitor of specific caspases, X-linked inhibitor of apoptosis (X-linked IAP or XIAP) can function as a cofactor in Smad, NF-kappaB, and JNK signaling pathways. However, caspases themselves have been shown to regulate the activity of a number of signaling cascades, raising the possibility that the effect of XIAP in these pathways is indirect. Here we examine this question by introducing point mutations in XIAP predicted to disrupt the ability of the molecule to bind to and inhibit caspases. We show that whereas these mutant variants of XIAP lost caspase-inhibitory activity, they maintained their ability to activate Smad, NF-kappaB, and JNK signaling pathways. Indeed, the signaling properties of the molecule were mapped to domains not directly involved in caspase binding and inhibition. The activation of NF-kappaB by XIAP was dependent on the E3 ubiquitin ligase activity of the RING domain. On the other hand, the ability of XIAP to activate Smad-dependent signaling was mapped to the third baculoviral IAP repeat (BIR) and loop regions of the molecule. Thus, the anti-apoptotic and signaling properties of XIAP can be uncoupled.
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PMID:Uncoupling of the signaling and caspase-inhibitory properties of X-linked inhibitor of apoptosis. 1470 99

The signal transduction cascade comprising Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and MAP kinase is a Ras effector pathway that mediates diverse cellular responses to environmental cues and contributes to Ras-dependent oncogenic transformation. Here we report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR, a scaffold/adaptor protein that couples activated Raf to its substrate MEK. IMP is a Ras-responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination, which releases the inhibition of Raf-MEK complex formation. Thus, Ras activates the MAP kinase cascade through simultaneous dual effector interactions: induction of Raf kinase activity and derepression of Raf-MEK complex formation. IMP depletion results in increased stimulus-dependent MEK activation without alterations in the timing or duration of the response. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus and providing a mechanism to allow adaptive behaviour of the cascade in chronic or complex signalling environments.
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PMID:Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. 1472 41

Ras interacts with numerous downstream effectors to transmit a diverse array of cellular signals. A new study shows that a protein known as Impedes Mitogenic signal Propagation, IMP, is an E3 ubiquitin ligase that binds Ras and modulates MAP kinase signaling by regulating the scaffolding activity of KSR.
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PMID:Signal transduction: implications for Ras-dependent ERK signaling. 1506 21

Phospholipase D (PLD) has been reported to generate survival signals that prevent apoptosis induced by serum withdrawal. We have now found that elevated expression of PLD also suppresses DNA damage-induced apoptosis. Since DNA damage-induced apoptosis is often mediated by p53, we examined the effect of elevated PLD expression on the regulation of p53 stabilization. We report here that PLD suppresses DNA damage-induced increases in p53 stabilization in cells where PLD has been shown to provide a survival signal. Elevated expression of PLD also led to increased expression of the p53 E3 ubiquitin ligase MDM2 and increased turnover of p53. PLD1-stimulated increases in MDM2 expression and suppression of p53 activation were blocked by inhibition of mTOR and the mitogen-activated protein kinase pathway. Although PLD did not activate the phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway activate the basal levels of PI3K activity were partially required for PLD1-induced increases in MDM2. These data provide evidence that survival signals generated by PLD involve suppression of the p53 response pathway.
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PMID:Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53. 1519 26

E2A transcription factors, E12 and E47, are important regulators of lymphocyte development. Notch signaling pathways have been shown to regulate E2A function by accelerating the degradation of E2A proteins through a mitogen-activated protein kinase-dependent and ubiquitin-mediated pathway. To further understand the mechanism underlying E2A ubiquitination and degradation, we conducted a yeast two-hybrid screen and identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as an E47 binding protein. Here, we show that CHIP associates with E2A proteins in vivo and that overexpression of CHIP induces E47 degradation in a phosphorylation-dependent manner. Conversely, knocking down CHIP with small interfering RNA alleviates Notch-induced E47 degradation. CHIP binds E47 through the E protein homology domains 2 and 3 (EHD2 and EHD3). This interaction between CHIP and E47 is independent of the U-box domain with E3 ubiquitin ligase activity but requires the chaperone binding tetratricopeptide repeats domain. The ability of CHIP to induce E47 ubiquitination and degradation correlates with its ability to bind E47. We propose that CHIP, together with its partner Hsc70, forms a preubiquitination complex (PUC) with E47 and Skp2, thus facilitating the interaction between E47 and Skp2. CHIP also associates with Cul1, which introduces PUC to the SCF E3 ligase complex, responsible for E47 ubiquitination. Therefore, CHIP plays a crucial role in the ubiquitination and degradation of E2A proteins.
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PMID:Notch-induced E2A degradation requires CHIP and Hsc70 as novel facilitators of ubiquitination. 1545 69


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