Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Determination of the involvement of MAP kinase cascades in signaling cell growth or differentiation is aided by the use of the inhibitors PD 098059 [2-(2'-amino-3'-methoxyphenyl)oxananphthalen-4-one] and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene], believed to be MEK-specific kinase inhibitors. We report here that the activity of kinase suppressor of ras (KSR-1), a kinase upstream of raf-1, is inhibited by both these compounds at concentrations similar to those that inhibit MEK-1. Further, in HL60 cells induced to differentiate with 1,25-dihydroxyvitamin D(3) raf-1 and p90RSK, but not ERK1/2, are coregulated, and their expression as well as monocytic differentiation is inhibited in parallel by PD 098059. Thus, in this system raf-1 is phosphorylated by KSR-1, and PD 098059 as well as U0126 inhibits this phosphorylation. This suggests great caution in the interpretation of experiments that utilize these pharmacological inhibitors of kinase activity as evidence for a role for the MEK--ERK module in ras or raf-1 signaling.
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PMID:Phosphorylation of raf-1 by kinase suppressor of ras is inhibited by "MEK-specific" inhibitors PD 098059 and U0126 in differentiating HL60 cells. 1147 55

The activity of kinase suppressor of ras (KSR), a kinase or a molecular scaffold upstream from Raf-1, is involved in the MEK/ERK MAP kinase cascade which can signal cell growth, survival, or differentiation, depending on the cellular context. We provide evidence here that KSR is upregulated in HL60 cells undergoing differentiation induced by low (0.3-3 nM) concentrations of 1,25-dihydroxyvitamin D(3) (1,25D(3)), and an antisense oligo (AS), but not a sense oligo, to KSR inhibits this differentiation. The inhibition of differentiation by AS-KSR oligo was less apparent when the concentration of 1,25D(3) was increased, suggesting that at the higher concentrations of 1,25D(3) KSR is not essential for the signaling of the differentiated phenotype. The reduced differentiation of HL60 cells exposed to AS-KSR was paralleled by reduced phosphorylation of Raf-1 Ser 259, and of p90RSK, used here as read-out for MAPK cascade activity. Conversely, ectopic expression of Flag-tagged wild type KSR potentiated the differentiation-inducing effects of low concentrations of 1,25D(3). Additional data suggest that the kinase activity of KSR is required for these effects, as transfection of a kinase inactive KSR construct did not significantly increase the 1,25D(3)-induced differentiation. Enzyme assays performed with KSR immunoprecipitated from 1,25D(3)-treated cells showed kinase activity when recombinant Raf-1 was used as the substrate, but not when the 1,25D(3)-treated cells were pretreated with AS-KSR oligos. Taken together, these data suggest that KSR participates in signaling of monocytic differentiation by augmenting the strength of the signal transmitted through Raf-1 to downstream targets.
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PMID:Kinase suppressor of RAS (KSR) amplifies the differentiation signal provided by low concentrations 1,25-dihydroxyvitamin D3. 1475 38

Kinase suppressor of ras (KSR) and MEKK3 (MAP kinase kinase kinase) are integral members of the MAP kinase pathway. We have recently identified a new isoform of the KSR family named human kinase suppressor of ras-2 (hKSR-2), and demonstrated that hKSR-2 negatively regulates Cot, a MAP3K family member which is important in inflammation and oncogenesis [P.L. Channavajhala, L. Wu, J.W. Cuozzo, J.P. Hall, W. Liu, L.L. Lin, Y. Zhang, J. Biol. Chem. 278 (2003) 47089-47097]. In this report, we provide evidence that hKSR-2 also regulates the activity of MEKK3 (another MAP3K family member) in HEK-293T cells. We demonstrate that hKSR-2 is a negative regulator of MEKK3-mediated activation of MAP kinase (specifically ERK and JNK) and NF-kappaB pathways, and concurrently inhibits MEKK3-mediated interleukin-8 production. We find that while hKSR-2 blocks MEKK3 activation, it has little to no effect on other members of the MAP3K family, including MEKK4, TAK1, and Ras-Raf, suggesting that its effects are selective.
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PMID:hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation. 1603 90