Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CRAF protein kinase regulates proliferative, differentiation, and survival signals from activated RAS proteins to downstream effectors, most often by inducing MEK/ERK activation. A well-established model of CRAF regulation involves RAS-mediated translocation of CRAF to the plasma membrane, where it is activated by a series of events including phosphorylation. Here we have discovered a new mode of regulation that occurs prior to this step. By creating a kinase-defective version of CRAF in mice or by use of the RAF inhibitor sorafenib, we show that CRAF must first undergo autophosphorylation of serine 621 (S621). Autophosphorylation occurs in cis, does not involve MEK/ERK activation, and is essential to ensure the correct folding and stability of the protein. In the absence of S621 phosphorylation, CRAF is degraded by the proteasome by mechanisms that do not uniquely rely on the E3 ubiquitin ligase CHIP.
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PMID:CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation. 1892 68

beta-Arrestins are ubiquitously expressed proteins that play important roles in receptor desensitization, endocytosis, proteosomal degradation, apoptosis and signaling. It has been reported that beta-Arrestin2 acts as a scaffold by directly interacting with the JNK3 isoform and recruiting MKK4 and the apoptosis-signaling kinase-1 (ASK1). Here, we report a novel function of beta-Arrestins in regulating H(2)O(2)-induced apoptosis. Our study demonstrates that beta-Arrestins physically associate with C-terminal domain of ASK1, and moreover, both over-expression and RNA interference (RNAi) experiments indicate that beta-Arrestins down-regulate ASK1 protein. In detail, beta-Arrestin-induced reduction of ASK1 protein is due to ubiquitination and proteasome-dependent degradation of ASK1 in response to association of beta-Arrestins and ASK1. Upon H(2)O(2) stimulation, the protein binding between beta-Arrestins and ASK1 increases and ASK1 degradation is expedited. In consequence, beta-Arrestins prevent ASK1-JNK signaling and as a result attenuate H(2)O(2)-induced apoptosis. Structurally, C-terminal domain of ASK1 is essential for beta-Arrestins and ASK1 association. We also found that CHIP is required for beta-Arrestins-induced ASK1 degradation, which suggested that beta-Arrestins function as a scaffold of ASK1 and CHIP, leading to CHIP-mediated ASK1 degradation. All these findings indicate that beta-Arrestins play a negative regulatory role in H(2)O(2)-induced apoptosis signaling through associating with ASK1 and CHIP and facilitating ASK1 degradation, which provides a new insight for analyzing the effects of beta-Arrestins on protecting cells from oxidative stress-induced apoptosis.
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PMID:beta-Arrestins facilitate ubiquitin-dependent degradation of apoptosis signal-regulating kinase 1 (ASK1) and attenuate H2O2-induced apoptosis. 1930 26

Our previous research had firstly shown that MM cells overexpressed IQGAP1 gene and activated Ras/Raf/MEK/ERK pathway. But the mechanism of IQGAP1 overexpression and IQGAP1 gene transcription regulation remains uncertain. The mechanism of IQGAP1 overexpression and transcriptional regulation of IQGAP1 gene in myeloma cells was explored in the study. Through bioinformatics analysis and prediction we predicted and screened transcription factor Sp1 as a possible upstream regulator of IQGAP1.The proliferation, cell cycle and downstream ERK1/2 and p-ERK1/2 proteins were detected after siRNA-IQGAP1 was transfected to myeloma cells. The expression of Sp1, p300, IQGAP1, p-ERK1/2 and ERK1/2 were detected after Sp1 and p300 were inhibited or overexpressed respectively. The dual-luciferase reporter system was used to detect the activity of IQGAP1 gene promoter. CHIP was used to detect the binding of the Sp1 and IQGAP1 promoter regions.CO-IP was used to explore the interaction between Sp1 and p300.The mRNA expression levels of Sp1,p300 and IQGAP1 of the myeloma patients were detected, and the correlation analysis of their mRNA expression levels were carried out. The results showed IQGAP1-siRNA inhibits cell proliferation, cell cycle, IQGAP1 expression and phosphorylation of ERK1/2 protein. Inhibition of Sp1 or p300 down-regulated ERK1/2 and IQGAP1 expression; overexpression of Sp1 or p300 up-regulated ERK1/2 and IQGAP1 expression; Sp1 and p300 had a positive regulation effect on IQGAP1.Over expression of Sp1 or p300 significantly increased activity of IQGAP1 gene promoter. The transcription factor Sp1 plays a regulatory role in the IQGAP1 promoter region. There is an interaction between Sp1 and p300 in myeloma cells. The mRNA expression levels of Sp1, IQGAP1 and p300 in MM samples showed a positive correlation. In summary IQGAP1 is required for cell proliferation in MM cells, and the transcription of Sp1/p300 complex regulates expression of IQGAP1 gene.
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PMID:The mechanism of SP1/p300 complex promotes proliferation of multiple myeloma cells through regulating IQGAP1 transcription. 3153 33