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)

Osteoclasts, cells that resorb bone, die once fully differentiated. Several factors including interleukin-1 (IL-1) have been shown to regulate the survival of mature osteoclasts. However, information on the mechanism underlying the regulation of osteoclast survival has been limited. In this study, we investigated the mechanism for the IL-1-stimulated survival of osteoclasts. Treatment of purified osteoclasts with IL-1alpha led to activation of the serine-threonine kinases Akt and ERK. Blocking the activation of Akt with LY294002, a specific inhibitor of the Akt up-stream molecule PI 3-kinase, or an with adenoviral vector for a dominant-negative form of Akt prevented the stimulation of osteoclast survival by IL-1alpha. PD98059, a specific inhibitor of the ERK-activating kinase MEK1, also abolished the effects of IL-1alpha on ERK activation and osteoclast survival. IL-1alpha reduced the apoptosis of osteoclasts by reducing caspase 3 activity. The IL-1alpha-mediated suppression of apoptosis was abolished by the PI 3-kinase/Akt or MEK1/ERK pathway inhibitor. These findings implicate the PI 3-kinase/Akt and ERK signaling pathways in the promotion of osteoclast survival by IL-1alpha.
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PMID:IL-1alpha stimulation of osteoclast survival through the PI 3-kinase/Akt and ERK pathways. 1175 48

Although conduit arteries develop hypertrophy after chronic NO synthesis blockade, resistance arteries remodel without hypertrophy under the same conditions. Similar findings have been described in essential hypertension. We postulated that this regional difference may be related to a heterogeneous effect of endogenous NO on proliferation along the vascular tree. Newly synthesized proteins were radiolabeled in vivo with [(3)H]L-leucine in basal conditions and during NO synthase inhibition, with or without PD98059 (inhibitor of the extracellular signal-regulated kinases [ERK] 1/2). Blocking the generation of NO by 3 different L-arginine analogues increased protein synthesis by an average of 75% in the aorta, in association with enhanced ERK 1/2 phosphorylation. PD98059 significantly reduced L-arginine analogue-induced protein synthesis and ERK 1/2 phosphorylation, confirming the involvement of ERK 1/2 as an important signaling element. In small arteries, L-arginine analogues did not influence the extent of protein synthesis, although phosphorylation of ERK 1/2 was also enhanced. To determine the role of NO in a condition of enhanced protein synthesis, angiotensin II was infused for 24 hours. Angiotensin II augmented protein synthesis in mesenteric arteries and the aorta, and was additive to NO synthase blockade in the aorta. In conclusion, endogenous NO exerts a tonic inhibitory influence on aortic growth, with limited impact on small arteries in basal and hypertrophic conditions. This heterogeneous role of NO on vascular growth may explain the heterogeneity of vascular remodeling observed in essential hypertension, a condition associated with endothelial dysfunction.
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PMID:Vessel-specific stimulation of protein synthesis by nitric oxide synthase inhibition: role of extracellular signal-regulated kinases 1/2. 1179 72

We hypothesize that in neurodegenerative disorders such as Alzheimer's disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3beta (GSK3beta), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependent inactivation of GSK3beta by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3beta were dependent on phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) because inhibitors of this pathway or infection with dominant negative Akt adenovirus blocked inactivation. Furthermore, treatment of neuronal cells with FGF1 resulted in ERK-independent Akt phosphorylation and beta-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3beta recombinant adenovirus-associated virus increased activity of GSK3beta and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3beta inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3beta by a pathway involving activation of the PI3K-Akt cascades.
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PMID:Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway. Implications for neuroprotection. 1209 87

Neuregulin-1 (NRG-1) is part of a family of proteins whose members are structurally related to epidermal growth factor. NRG-1 induces cell proliferation through a high-affinity receptor complex composed of a heterodimer of human epidermal growth factor-like receptor (HER) 2 and 3. In this study, we show that NRG-1 activates the Janus kinases (JAK) and signal transducer and activator of transcription proteins (STAT). NRG-1 induced a rapid and transient increase in tyrosine phosphorylation of TYK2 and JAK3, but not JAK1 or JAK2, and induced STAT3 and STAT5 tyrosine phosphorylation. Upon phosphorylation, STAT3 translocated to the nucleus within 1 h. Activation of the JAK-STAT pathway was dependent on HER2/HER3 heterodimerization and was necessary for NRG-1-induced proliferation. Inhibition of HER2's ability to dimerize using the HER2-specific antibody 2C4 completely blocked NRG-1-induced JAK3, TYK2, STAT3, and STAT5 tyrosine phosphorylation. Blocking the JAK-STAT pathway with a specific JAK-STAT pathway inhibitor, AG490, inhibited NRG-1-induced JAK and STAT phosphorylation and cell proliferation. These data suggest that NRG-1 activates the JAK-STAT signal transduction pathway through its high-affinity receptor, the HER2/HER3 heterodimer. This pathway plays an important role in NRG-1-stimulated proliferation of pulmonary epithelial cells.
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PMID:Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. 1220 92

Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling induces the expression of Runx2, a key transcription factor in osteoblast differentiation, but little is known about the molecular signaling mechanisms that mediate this. Here we examined the role of the protein kinase C (PKC) pathway in regulating Runx2 gene expression and its transactivation function. Treatment with FGF2 or FGF4, or transfection with a vector expressing a mutant FGFR2 that is constitutively activated in the absence of ligand, strongly stimulates Runx2 expression. Electrophoretic mobility shift assays also showed that FGF2 treatment increases the specific binding of Runx2 to the cognate response element in the osteocalcin gene promoter. Blocking PKC completely inhibited FGF2-induced Runx2 expression, whereas mitogen-activate protein kinase inhibitors had no effect. The FGF/FGFR-stimulated 6xOSE2 promoter activity was also blocked by inhibiting PKC, as was the FGF2 stimulation of the DNA-binding activity of Runx2. Experiments with PKC isoform-specific inhibitors and dominant negative isoforms of PKC indicate that PKCdelta is one of key isoforms involved in the FGF2-stimulated Runx2 expression. In addition, experiments with Runx2-knockout cells showed that, although the PKC pathway largely regulates FGF2-stimulated Runx2 activity by up-regulating Runx2 expression, it also modifies Runx2 protein post-translationally and thereby increases its transcriptional activity. Thus, we show for the first time that FGF/FGFR signaling stimulates the DNA-binding and transcriptional activities of Runx2 as well as its expression, and these are largely regulated by the PKC pathway.
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PMID:The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. 1240 80

MAP kinase pathways comprise a group of parallel protein phosphorylation cascades, which are involved in signaling triggered by a variety of stimuli. Previous findings suggested that the ERK and the JNK pathways have opposing roles in regulating proliferation and survival or apoptosis and that apoptosis can be promoted by inhibiting the ERK pathway or by activation of the JNK pathway. In order to test this hypothesis and explore whether it can be exploited as a strategy for killing human cancer cells, we used gene transfer experiments with a range of cancer cell lines. We expressed the catalytic fragment of human MEKK1 to activate JNK and the Ras-binding domain (RBD) of Raf-1 to inhibit the Ras-ERK pathway. In addition, we designed several RBD-MEKK1 fusion proteins aiming to simultaneously activate the JNK and block the ERK pathway. We found that the MEKK1 proteins as well as the RBD alone could reduce colony formation in all cell lines. The survival time of MEKK1-expressing cells depended on the cell line. In HeLa cells, survival could be prolonged by inhibition of caspases but not by coexpression of the anti-apoptotic protein Bcl-2. Due to a lower kinase activity the RBD-MEKK1 fusion proteins were less effective in apoptosis induction than the MEKK1 kinase domain alone. Using mutant forms of Ras and Raf-1 we could show that the reduced kinase activity of RBD-MEKK1 fusion proteins was caused by binding to the Ras protein. The expression of lethal doses of MEKK1 resulted in a strong activation of all three major MAP kinase families JNK, ERK, and p38. Blocking these pathways either by coexpressing a dominant negative form of MKK4 or with inhibitors of MEK or p38 failed to inhibit apoptosis. This suggests that MEKK1 induces apoptosis by causing a general deregulation of MAP kinase signaling rather than by the activation of a single pathway.
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PMID:The kinase domain of MEKK1 induces apoptosis by dysregulation of MAP kinase pathways. 1256 21

Fibroblast growth factors (FGFs) exert diverse effects resulting from their interaction with cognate receptors on target cells. Our current study was designed to examine the local production and action of two specific stromal-epithelial cell mediatory factors, keratinocyte growth factor (KGF) and FGF-10, in human endometrial carcinoma cells. The RT-PCR method was used to determine gene expression of KGF, FGF-10, and KGF receptor in human endometrial carcinoma cells (HEC-1) and human endometrial stromal cells. KGF mRNAs were expressed in both of these cell types. On the other hand, FGF-10 mRNA was detected only in the endometrial stromal cells, and KGF receptor mRNA was observed in the HEC-1 cells. The novel finding of the present study is that KGF is expressed in carcinoma cells and FGF-10 is expressed in human endometrial stromal cells. The distinct phosphorylation of ERK-1 and -2 (ERK1/2), which are members of the MAPK family, was observed when HEC-1 cells were treated with KGF or FGF-10. KGF and FGF-10 could induce the prompt phosphorylation of ERK1/2 and consequently stimulate DNA synthesis. KGF and FGF-10 did not activate the phosphorylation of Akt, protein kinase C, or signal transducer and activator of transcription-3. Blocking the MAPK pathway with the specific methyl ethyl ketone 1/2 inhibitor (U0126) completely neutralized the enhancement of cell proliferation induced by KGF and FGF-10. In addition, KGF and FGF-10 activated expressions of downstream nuclear transcription factors, such as Elk-1 and c-myc, but not c-fos. These results demonstrate for the first time that KGF and FGF-10 are capable of stimulating the growth of endometrial carcinoma cells via activating MAPK pathway through autocrine/paracrine fashion.
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PMID:Activation of mitogen-activated protein kinase pathway by keratinocyte growth factor or fibroblast growth factor-10 promotes cell proliferation in human endometrial carcinoma cells. 1257 12

The abnormal accumulation of methylglyoxal (MG), a physiological glucose metabolite, is strongly related to the development of diabetic complications by affecting the metabolism and functions of organs and tissues. These disturbances could modify the cell response to hormones and growth factors, including insulin-like growth factor-1 (IGF-I). In this study, we investigated the effect of MG on IGF-I-induced cell proliferation and the mechanism of the effect in two cell lines, a human embryonic kidney cell line (HEK293), and a mouse fibroblast cell line (NIH3T3). MG rendered these cells resistant to the mitogenic action of IGF-I, and this was associated with stronger and prolonged activation of ERK and over-expression of P21(Waf1/Cip1). The synergistic effect of MG with IGF-I in activation of ERK was completely abolished by PD98059 but not by a specific PI3K inhibitor, LY294002, or a specific PKC inhibitor, bisindolylmaleimide. Blocking of Raf-1 activity by expression of a dominant negative form of Raf-1 did not reduce the enhancing effect of MG on IGF-I-induced activation of ERK. However, transfection of a catalytically inactive form of MEKK1 resulted in inactivation of the MG-induced activation of ERK and partial inhibition of the enhanced activation of ERK and over-expression of p21(Waf1/Cip1) induced by co-stimulation of MG and IGF-I. These results suggested that the alteration of intracellular milieu induced by MG through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway resulted in the modification of cell response to IGF-I for p21(Waf1/Cip1)-mediated growth arrest, which may be one of the crucial mechanisms for MG to promote the development of chronic clinical complications in diabetes.
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PMID:Involvement of MEKK1/ERK/P21Waf1/Cip1 signal transduction pathway in inhibition of IGF-I-mediated cell growth response by methylglyoxal. 1264 5

We have examined highly purified osteoclasts that were generated in vitro from murine co-culture of marrow precursors with stromal support cells and have found evidence of activation of the MEK/ERK and AKT/NFkappaB survival pathways. Many mature marrow-derived osteoclasts survived for at least 48 h in culture whether or not they are maintained with stromal cells. Moreover, supplementing purified osteoclasts with RANKL and/or M-CSF had no impact on their survival pattern. In addition, spleen-derived osteoclasts generated with RANKL and M-CSF treatment exhibited a similar survival pattern. Blocking MEK, AKT, or NFkappaB activity resulted in apoptosis of many, but not all, of the osteoclasts in purified marrow-derived osteoclasts, marrow-derived osteoclasts co-cultured with stromal cells, and spleen-derived osteoclasts maintained with RANKL and M-CSF. These data support that both the MEK/ERK and AKT/NFkappaB pathways contribute to osteoclast survival. Since PI3K has been shown to activate either of these pathways, we have examined its role in osteoclast survival. PI3K inhibition caused apoptosis of nearly all osteoclasts in purified and co-cultured marrow-derived osteoclasts and spleen-derived osteoclasts maintained with RANKL and M-CSF. Interestingly, in marrow-derived co-cultures, the apoptotic response was restricted to osteoclasts as there was no evidence of stromal support cell apoptosis. PI3K inhibition also blocked MEK1/2, ERK1/2, and AKT phosphorylation and NFkappaB activation in purified osteoclasts. Simultaneous blockage of both AKT and MEK1/2 caused rapid apoptosis of nearly all osteoclasts, mimicking the response to PI3K inhibition. These data reveal that PI3K coordinately activates two distinct survival pathways that are both important in osteoclast survival.
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PMID:Phosphatidylinositol 3-kinase coordinately activates the MEK/ERK and AKT/NFkappaB pathways to maintain osteoclast survival. 1268 17

Focal adhesion complexes are actin-rich, cytoskeletal structures that mediate cell adhesion to the substratum and also selectively regulate signal transduction pathways required for interleukin (IL)-1beta signaling to the MAP kinase, ERK. IL-1-induced ERK activation is markedly diminished in fibroblasts deprived of focal adhesions whereas activation of p38 and JNK is unaffected. While IL-1 signaling is known to involve the activity of protein and lipid kinases including MAP kinases, FAK, and PI3K, little is known about the role of phosphatases in the regulation of IL-1 signal generation and attenuation. Here we demonstrate that SHP-2, a protein tyrosine phosphatase present in focal adhesions, modulates IL-1-induced ERK activation and the transient actin stress fiber disorganization that occurs following IL-1 treatment in human gingival fibroblasts. Using a combination of immunoblotting, immunoprecipitation, and immunostaining we show that SHP-2 is present in nascent focal adhesions and undergoes phosphorylation on tyrosine 542 in response to IL-1 stimulation. Blocking anti-SHP-2 antibodies, electoporated into the cytosol of fibroblasts, inhibited IL-1-induced ERK activation, actin filament assembly, and cell contraction, indicating a role for SHP-2 in these processes. In summary, our data indicate that SHP-2, a focal adhesion-associated protein, participates in IL-1-induced ERK activation likely via an adaptor function.
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PMID:The protein tyrosine phosphatase SHP-2 regulates interleukin-1-induced ERK activation in fibroblasts. 1272 Dec 96


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