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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MAPKKK5/ASK1 activates c-Jun N-terminal kinase (JNK) and p38 kinase signaling pathways and induces apoptosis when expressed in stably transfected cells. Using MAPKKK5 as bait in yeast two-hybrid screening, a novel protein that interacts with MAPKKK5 was identified and cloned. This novel protein is predicted to contain all 11 kinase subdomains and shares 45% amino acid identity with MAPKKK5 and thus is designated MAPKKK6. The interaction of MAPKKK6 with MAPKKK5 in vivo was confirmed by coexpression of MAPKKK5 and MAPKKK6 in 293 cells followed by immunoprecipitation. In contrast to MAPKKK5, which activated both JNK and p38 kinase pathways, MAPKKK6 only weakly activated JNK but not ERK or p38 kinase pathways.
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PMID:MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5. 987 15

The insulin receptor (IR) and the insulin-like growth factor receptor I (IGF-IR) have different functions in cell growth, apoptosis, differentation, and transformation. Although some of these differences may be explained by the relative level of receptor expression and receptor structure (alpha and beta subunits), they may also be attributed to differences in intracellular signals generated by insulin and IGF-I. The presence of hybrid receptors (IR alphabeta subunits and IGF-IR alphabeta subunits) making up the heterotetramers has added a new dimension to our understanding of the functional roles of these receptors. However, to date the results of efforts to understand the differences between these two closely related receptors have indicated mostly similarities. For example, both receptors utilize IRS-1/IRS-2 and Shc as immediate downstream adaptors, leading to activation of the Ras, Raf, ERK kinases and PI-3 kinase pathways. We have used the yeast two hybrid system to identify proteins which bind to the activated IGF-IR but not to the IR. The cytoplasmic domain of the IGF-IR was used to screen a human fetal brain library and two isoforms of the 14-3-3 family were identified. 14-3-3 proteins are a highly conserved family of proteins which have recently been shown to interact with other components of the mitogenic and apoptotic signaling pathways, including Raf, BAD, Bcr/Bcr-Abl, middle-T antigen, Ksr, PKC, PI-3 kinase, ASK1 kinase, and cdc25C phosphatase. We also identified human Grb10, an adaptor protein with SH2 domain associated with the IGF-IR beta subunit. Smith's laboratory showed that Grb10 preferentially binds to the IR in intact cells. Using the interaction trap screen (active cytoplasmic domain of the IGF-IR) 55PIK and SOCS-2 proteins were also identified. However, 55PIK and SOCS-2 also interact with the IR in the yeast two hybrid system. These studies raise the possibility that 14-3-3 and Grb10 may play a role in insulin and IGF-I signal transduction and may underlie the observed differences.
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PMID:Differential regulation of signaling pathways for insulin and insulin-like growth factor I. 1045 81

Normal flower development likely requires both specific and general regulators. We have isolated an Arabidopsis mutant ask1-1 (for -Arabidopsis skp1-like1-1), which exhibits defects in both vegetative and reproductive development. In the ask1-1mutant, rosette leaf growth is reduced, resulting in smaller than normal rosette leaves, and internodes in the floral stem are shorter than normal. Examination of cell sizes in these organs indicates that cell expansion is normal in the mutant, but cell number is reduced. In the mutant, the numbers of petals and stamens are reduced, and many flowers have one or more petals with a reduced size. In addition, all mutant flowers have short stamen filaments. Furthermore, petal/stamen chimeric organs are found in many flowers. These results indicate that the ASK1 gene affects the size of vegetative and floral organs. The ask1 floral phenotype resembles somewhat that of the Arabidopsis ufo mutants in that both genes affect whorls 2 and 3. We therefore tested for possible interactions between ASK1 and UFO by analyzing the phenotypes of ufo-2 ask1-1 double mutant plants. In these plants, vegetative development is similar to that of the ask1-1 single mutant, whereas the floral defects are more severe than those in either single mutant. Interior to the first whorl, the double mutant flowers have more sepals or sepal-like organs than are found in ufo-2, and less petals than ask1-1. Our results suggest that ASK1 interacts with UFO to control floral organ identity in whorls 2 and 3. This is very intriguing because ASK1 is very similar in sequence to the yeast SKP1 protein and UFO contains an F-box, a motif known to interact with SKP1 in yeast. Although the precise mechanism of ASK1 and UFO action is unknown, our results support the hypothesis that these two proteins physically interact in vivo.
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PMID:The ASK1 gene regulates development and interacts with the UFO gene to control floral organ identity in Arabidopsis. 1052 62

Matrix metalloproteinase-1 (MMP-1) plays an important role in the degradation of extracellular matrix components under several physiological and pathological conditions. The expression of this protease is upregulated by mitogenic growth factors and proinflammatory cytokines, which have been shown to activate different sets of mitogen-activated protein (MAP) kinase pathways. Here we provide evidence that activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) or the p38 MAP kinase pathway is sufficient to induce transcription from the MMP-1 promoter in human primary fibroblasts, whereas modulation of mRNA stability seems to be of minor importance. Upregulation of MMP-1 expression by mitogenic or inflammatory stimuli is blocked by specific small molecular weight inhibitors of the ERK pathway or the p38 pathway, respectively, and constitutively active kinases within the ERK1/2 pathway (MEKK1, MEK1) or the p38 pathway (ASK1, MEKK1, MKK3) are potent activators of the MMP-1 promoter. The current study provides evidence that distinct extracellular signals leading to upregulation of MMP-1 expression in fibroblasts are relayed independently through different MAP kinase pathways and are integrated at the level of the promoter.
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PMID:Independent role of p38 and ERK1/2 mitogen-activated kinases in the upregulation of matrix metalloproteinase-1. 1091 95

The Ser/Thr kinase Raf-1 is a protooncogene product that is a central component in many signaling pathways involved in normal cell growth and oncogenic transformation. Upon activation, Raf-1 phosphorylates mitogen-activated protein kinase kinase (MEK), which in turn activates mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERKs), leading to the propagation of signals. Depending on specific stimuli and cellular environment, the Raf-1--MEK--ERK cascade regulates diverse cellular processes such as proliferation, differentiation, and apoptosis. Here, we describe a MEK--ERK-independent prosurvival function of Raf-1. We found that Raf-1 interacts with the proapoptotic, stress-activated protein kinase ASK1 (apoptosis signal-regulating kinase 1) in vitro and in vivo. Deletion analysis localized the Raf-1 binding site to the N-terminal regulatory fragment of ASK1. This interaction allows Raf-1 to act independently of the MEK--ERK pathway to inhibit apoptosis. Furthermore, catalytically inactive forms of Raf-1 can mimic the wild-type effect, raising the possibility of a kinase-independent function of Raf-1. Thus, Raf-1 may promote cell survival through its protein-protein interactions in addition to its established MEK kinase function.
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PMID:Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. 1142 28

The human lymphotoxin beta receptor (LTbetaR), a member of the tumor necrosis factor (TNF) receptor superfamily, is essential for not only the development and organization of secondary lymphoid tissues, but also for chemokine release. Even though LTbetaR was shown to recruit TNF-receptor-associated factor (TRAF) 2, 3, and 5, and to induce cell apoptosis or NF-kappaB activation, however, the downstream signaling leading to chemokine expression is not illustrated yet. In this study, we find that overexpression of LTbetaR in HEK293 cells increases IL-8 promoter activity and leads to IL-8 release. LTbetaR-induced IL-8 gene expression requires NF-kappaB (-80 to -71) and AP-1 (-126 to -12) binding sites located in IL-8 promoter, and NF-kappaB is more crucial than AP-1 for IL-8 gene expression. Reporter assay with dominant-negative mutants of TRAFs reveals that TRAF2, 3, and 5, as well as the downstream signal molecules NIK, IKKalpha, and IKKbeta, are involved in IL-8 gene expression. LTbetaR-mediated IL-8 response was inhibited by the dominant-negative mutants of ASK1, MKK4, MKK7, and JNK, but not by those of MEKK1, TAK1, MEK, ERK, and p38 MAPK. This suggests that IL-8 induction by LTbetaR is via TRAFs-elicited signaling pathways, including NIK/IKK-dependent NF-kappaB activation and ASK/MKK/JNK-dependent AP-1 activation.
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PMID:Lymphotoxin beta receptor induces interleukin 8 gene expression via NF-kappaB and AP-1 activation. 1216 72

Chemotaxis mediated by chemokine receptors such as CXCR4 plays a key role in lymphocyte homing and hematopoiesis as well as in breast cancer metastasis. We have demonstrated previously that beta-arrestin2 functions to attenuate CXCR4-mediated G protein activation and to enhance CXCR4 internalization. Here we show further that the expression of beta-arrestin2 in both HeLa and human embryonic kidney 293 cells significantly enhances the chemotactic efficacy of stromal cell-derived factor 1alpha, the specific agonist of CXCR4, whereas the suppression of beta-arrestin2 endogenous expression by antisense or RNA-mediated interference technology considerably attenuates stromal cell-derived factor 1alpha-induced cell migration. Expression of beta-arrestin2 also augmented chemokine receptor CCR5-mediated but not epidermal growth factor receptor-mediated chemotaxis, indicating the specific effect of beta-arrestin2. Further analysis reveals that expression of beta-arrestin2 strengthened CXCR4-mediated activation of both p38 MAPK and ERK, and the suppression of beta-arrestin2 expression blocked the activation of two kinases. Interestingly, inhibition of p38 MAPK activation (but not ERK activation) by its inhibitors or by expression of a dominant-negative mutant of p38 MAPK effectively blocked the chemotactic effect of beta-arrestin2. Expression of a dominant-negative mutant of ASK1 also exerted the similar blocking effect. The results of our study suggest that beta-arrestin2 can function not only as a regulator of CXCR4 signaling but also as a mediator of stromal cell-derived factor 1alpha-induced chemotaxis and that this activity probably occurs via the ASK1/p38 MAPK pathway.
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PMID:Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. 1237 Jan 87

Reactive oxygen species (ROS) during normal metabolism signal cells to stimulate proliferation or to cause cellular damages, depending on a specific concentration. Energy restriction (ER) increases life span in animals, which can explain an effective modulator for reducing oxidative stress. Oxidative stress can result from a decrease in the protection against ROS. The deleterious effects of oxidative stress generally occur after exposure to a relatively high concentration of ROS. Alternatively, it has been suggested that a low concentration of ROS can exert important physiological roles in cellular signaling and proliferation. Signal pathways are crucial for cell survival or death. It is generally acceptable that aged cells have less response to stresses such as ROS than young cells. Oxidative stresses induce JNK and p38 kinase pathways regulated by redox regulatory proteins: thioredoxin and glutathione s-transferase, respectively. Antioxidants such as selenium block apoptosis induced by ROS through blocking apoptotic signal ASK1 and stimulating survival signal Akt activity. Old hepatocytes are more susceptible to ROS-induced apoptosis than young hepatocytes, which is associated with low expression of ERK and Akt kinases. Pharmacological inhibition of ERK and Akt activation in the young cells markedly increase their sensitivity to H(2)O(2), and ER, by preventing loss of ERK and Akt activities, enhances survival of old hepatocytes to a level similar to those of young cells. Expressions of signal pathways such as survival and apoptotic signals can regulate cells' fate and aging process. Further studies on the interaction of signal pathways may change the scientific direction of the study of aging.
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PMID:Dose effect of oxidative stress on signal transduction in aging. 1247 Aug 97

The present study was performed to examine mitogen-activated protein kinase associated pathways in mediation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cell apoptosis in cultured Jurkat T cells. TCDD significantly decreased cell viability in a concentration-dependent manner (P<0.05 at 10-300 nM). TCDD (10 nM) also time-dependently decreased cell viability (P<0.05 at 12-48 hr). c-Jun NH2-terminal kinase was significantly phosphorylated with TCDD treatment in a time dependent manner. p38 Mitogen-activated protein kinase was not significantly changed with TCDD treatment. Extracellular signal-regulated protein kinase was significantly phosphorylated with TCDD treatment for 8 hr and gradually returned to baseline. TCDD induced up-regulation of ASK1 and C-Jun, which are up- and down-stream of JNK, respectively, and up-regulation of cytosolic cytochrome c and caspase-3. These results demonstrate that MAPK signaling pathways including JNK and ERK 1/2, are activated with the treatment of TCDD in Jurkat T cells, which suggest that MAPK pathways may be involved in TCDD-induced cell death.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of mitogen-activated protein kinase signaling pathway in Jurkat T cells. 1462 43

Specific protein degradation has been observed in several aspects of development and differentiation in many organisms. One example of such proteolysis is regulated by protein polyubiquitination that is promoted by the SCF complex consisting of Skp1, cullin, and an F-box protein. We examined the activities of the Arabidopsis Skp1-related proteins (ASKs). Among 19 annotated ASK genes, we isolated 16 of the corresponding cDNAs (ASK1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19), and examined their gene products for interactions with 24 representatives of F-box proteins carrying various classes of the C-terminal domains using the yeast two-hybrid system. As a result, we found diverse binding specificities: ASK1, ASK2, ASK11 and ASK12 interacted well with COI1, FKF1, UFO-like protein, LRR-containing F-box proteins, and other F-box proteins with unknown C-terminal motifs. We also observed specific interaction between F-box proteins and ASK3, ASK9, ASK13, ASK14, ASK16 and ASK18. In contrast, we detected no interaction between any of the 12 ASK proteins and F-box proteins containing CRFA, CRFB or CRFC domains. Both histochemical and RT-PCR analysis of eight ASK genes expression revealed unique expression patterns for the respective genes.
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PMID:Expression and interaction analysis of Arabidopsis Skp1-related genes. 1474 89


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