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)

Lung growth and remodeling are modulated by mechanical stress, with fibroblasts thought to play a leading role. Little mechanistic information is available about how lung fibroblasts respond to mechanical stress. We exposed cultured lung fibroblasts to tonic stretch and measured changes in phosphorylation status of mitogen-activated protein kinases (MAPKs), selected receptor tyrosine kinases (RTKs), and phospholipase Cgamma1 (PLCgamma1) and activation of the small G-protein Ras. Human lung fibroblasts (LFs) were seeded on matrix-coated silicone membranes and exposed to equibiaxial 10 to 40% static stretch or 20% contraction. LFs were stimulated with EGF, FGF2, or PDGF-BB or exposed to stretch in the presence of inhibitors of EGFR (AG1478), FGFR (PD173074), and PDGFR (AG1296). Phospho-MAPK, phospho-RTK, and phospho-PLCgamma1 levels were measured by Western blotting. Active GTP-Ras was quantified by immunoblotting after pull-down with a glutathione S-transferase-Raf-RBD construct. Normalized p-ERK1/2, p-JNK, and p-p38 levels increased after stretch but not contraction. Ligands to RTKs broadly stimulated MAPKs, with the responses to EGF and PDGF most similar to stretch in terms of magnitude and rank order of MAPK responses. Stretching cells failed to elicit measurable activation of EGFR, FGFR (FRS2alpha phosphorylation), or PDGFR. Potent inhibitors of the kinase activity of each receptor failed to attenuate stretch-induced MAPK activation. PLCgamma1 and Ras, prominent effectors downstream of RTKs, were not activated by stretch. Our findings demonstrate that MAPKs are potently activated by stretch in lung fibroblasts, but, in contrast to stress responses observed in other cell types, RTKs are not necessary for stretch-induced MAPK activation in LFs.
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PMID:Stretch-induced mitogen-activated protein kinase activation in lung fibroblasts is independent of receptor tyrosine kinases. 1968 8

Vascular endothelial growth factor receptor 2 (VEGFR2) plays crucial roles in vasculogenesis, a process involving cell proliferation, migration and differentiation. However, the molecular mechanism by which VEGFR2 signaling directs vascular endothelial differentiation of VEGFR2(+) mesodermal progenitors is not well understood. In this study, we examined the signal transduction pathway downstream of VEGFR2 for endothelial differentiation using an in vitro differentiation system of mouse embryonic stem-cell-derived VEGFR2(+) cells. Using chimeric receptors composed of VEGFR2 and VEGFR3, the third member of the VEGFR family, we found that signaling through tyrosine 1175 (Y1175, corresponding to mouse Y1173) of VEGFR2 is crucial for two processes of endothelial differentiation: endothelial specification of VEGFR2(+) progenitors, and subsequent survival of endothelial cells (ECs). Furthermore, we found that phospholipase Cgamma1 (PLCgamma1), which interacts with VEGFR2 through phosphorylated Y1175, is an inducer of endothelial specification. In contrast to VEGFR2, VEGFR3 does not transmit a signal for endothelial differentiation of VEGFR2(+) cells. We found that VEGFR3 does not activate PLCgamma1, although VEGFR3 has the ability to support endothelial cell survival. Taken together, these findings indicate that VEGFR2-PLCgamma1 signal relay gives rise to the unique function of VEGFR2, thus enabling endothelial differentiation from vascular progenitors.
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PMID:VEGFR2-PLCgamma1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells. 1970 81

A mutation of Atp2a2 gene encoding the sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) causes Darier's disease in human and null mutation in one copy of Atp2a2 leads to a high incidence of squamous cell tumor in a mouse model. In SERCA2 heterozygote (SERCA2(+/-)) mice keratinocytes, mechanisms involved in partial depletion of SERCA2 gene and its related tumor induction have not been studied. In this study, we investigated Ca(2+) signaling and differential gene expression in primary cultured keratinocytes from SERCA2(+/-) mice. SERCA2(+/-) keratinocytes showed reduced initial increases in intracellular concentration of calcium in response to ATP, a G-protein coupled receptor agonist, and higher store-operated Ca(2+) entry with the treatment of thapsigargin, an inhibitor of SERCA, compared to wild type kerationcytes. Protein expressions of plasma membrane Ca(2+) ATPases, NFATc1, phosphorylated ERK, JNK, and phospholipase gamma1 were increased in SERCA2(+/-) keratinocytes. Using the gene fishing system, we first found in SERCA2(+/-) keratinocytes that gene level of tumor-associated calcium signal transducer 1, crystalline alphaB, procollagen XVIII alpha1, and nuclear factor I-B were increased. Expression of involucrin, a marker of keratinocyte differentiation, was decreased in SERCA2(+/-) keratinocytes. These results suggest that the alterations of Ca(2+) signaling by SERCA2 haploinsufficiency alternate the gene expression of tumor induction and differentiation in keratinocytes.
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PMID:Markers of squamous cell carcinoma in sarco/endoplasmic reticulum Ca2+ ATPase 2 heterozygote mice keratinocytes. 1984 Aug 14

Brain injury induces the expression of well-known cytokines, such as tumor necrosis factor-alpha (TNFalpha), and other, which functions are less understood, as secreted phospholipase A(2) group IIA (sPLA(2)-IIA). Since in pathological processes, cytokines function coordinately in networks, to further explore the actions of sPLA(2)-IIA in tumorigenesis, we investigated the effect of sPLA(2)-IIA in the presence of TNFalpha in human 1321N1 astrocytoma cells. In these cells, TNFalpha activates the apoptotic programme that is accompanied of cytoskeleton changes; however, simultaneous treatment with sPLA(2)-IIA prevents TNFalpha-mediated apoptosis and reverses the modification of the markers associated to this response. In fact, the mitogenic activity elicited by the phospholipase alone is preserved. This inhibitory effect is not found in other TNFalpha-mediated responses, even a functional cooperation is observed on COX-2 protein induction. The cross-talk between TNFalpha and sPLA(2)-IIA is associated with ERK activity since its pharmacological inhibition attenuates both synergistic and inhibitory responses. We have also observed that upon sPLA(2)-IIA stimulation, endogenous ERK has the capacity to bind and phosphorylate sequences present within the cytoplasmic domain of TNFR1/CD120a. These findings thus indicate that sPLA(2)-IIA and TNFalpha transduction pathways interact to modulate inflammatory responses and provide additional insights about the capacity of sPLA(2)-IIA to promote apoptosis resistance in astrocytoma cells.
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PMID:Inflammatory protein sPLA(2)-IIA abrogates TNFalpha-induced apoptosis in human astroglioma cells: Crucial role of ERK. 1985 87

Cross-linking of NK activating receptors activates phospholipase-gamma and subsequently induces diacylglycerol and Ca(2+) as second messengers of signal transduction. Previous studies reported that Ras guanyl nucleotide-releasing protein (RasGRP) 1, which is activated by diacylglycerol and Ca(2+), is crucial for TCR-mediated Ras-ERK activation. We now report that RasGRP1, which can also be detected in human NK cells, plays an essential role in NK cell effector functions. To examine the role of RasGRP1 in NK cell functions, the expression of RasGRP1 was suppressed using RNA interference. Knockdown of RasGRP1 significantly blocked ITAM-dependent cytokine production as well as NK cytotoxicity. Biochemically, RasGRP1-knockdown NK cells showed markedly decreased ability to activate Ras, ERK, and JNK. Activation of the Ras-MAPK pathway was independently shown to be indispensable for NK cell effector functions via the use of specific pharmacological inhibitors. Our results reveal that RasGRP1 is required for the activation of the Ras-MAPK pathway leading to NK cell effector functions. Moreover, our data suggest that RasGRP1 might act as an important bridge between phospholipase-gamma activation and NK cell effector functions via the Ras-MAPK pathway.
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PMID:RasGRP1 is required for human NK cell function. 1993 60

Calcineurin inhibitors (CNI) are powerful immunomodulatory agents that produce marked renal dysfunction due in part to endothelin-1-mediated reductions in renal blood flow. Ligand-stimulated Gq protein signaling promotes the contraction of smooth muscle cells via phospholipase Cbeta-mediated stimulation of cytosolic calcium release. RGS4 is a GTPase activating protein that promotes the deactivation of Gq and Gi family members. To investigate the role of G protein-mediated signaling in the pathogenesis of CNI-mediated renal injury, we used mice deficient for RGS4 (rgs4(-/-)). Compared to congenic wild type control animals, rgs4(-/-) mice were intolerant of the CNI, cyclosporine (CyA), rapidly developing fatal renal failure. Rgs4(-/-) mice exhibited markedly reduced renal blood flow after CyA treatment when compared to congenic wild type control mice as measured by magnetic resonance imaging (MRI). Hypoperfusion was reversed by coadministration of CyA with the endothelin antagonist, bosentan. The MAPK/ERK pathway was activated by cyclosporine administration and was inhibited by cotreatment with bosentan. These results show that endothelin-1-mediated Gq protein signaling plays a key role in the pathogenesis of vasoconstrictive renal injury and that RGS4 antagonizes the deleterious effects of excess endothelin receptor activation in the kidney.
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PMID:RGS4 controls renal blood flow and inhibits cyclosporine-mediated nephrotoxicity. 1995 25

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are broadly expressed in the developing and adult mammalian brain. BDNF/TrkB-stimulated intracellular signaling is critical for neuronal survival, morphogenesis, and plasticity. It is well known that binding of BDNF to TrkB elicits various intracellular signaling pathways, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), phospholipase Cg (PLCg), and phosphoinositide 3-kinase (PI3K) pathways, and that BDNF exerts biological effects on neurons via activation of similar mechanisms. In addition to TrkB, a low-affinity receptor p75 is also involved in neuronal survival and plasticity. BDNF affects neurons positively or negatively through various intracellular signaling pathways triggered by activation of TrkB or p75. From a clinical standpoint, roles of BDNF have been implicated in the pathophysiology of various brain diseases. The stress-induced steroid hormone, glucocorticoid, and BDNF are putatively associated with the pathophysiology of depression. Recent reports, including our studies, demonstrate possible crosstalk between glucocorticoid- and BDNF/TrkB-mediated signaling. Here, we present a broad overview of the current knowledge concerning BDNF action and associated intracellular signaling as it relates to neuronal protection, synaptic function, and morphological change. Furthermore, understanding the secretion and intracellular dynamics of BDNF proteins is critical as the fate of secreted BDNF may contribute to differences in neuronal response.
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PMID:BDNF function and intracellular signaling in neurons. 2001 10

Activation of fibroblast growth factor (FGF) receptors (FGFRs) both by FGFs and by the neural cell adhesion molecule (NCAM) is crucial in the development and function of the nervous system. We found that FGFR substrate 2alpha (FRS2alpha), Src homologous and collagen A (ShcA), and phospholipase-Cgamma (PLCgamma) were all required for neurite outgrowth from cerebellar granule neurons (CGNs) induced by FGF1 and FGL (an NCAM-derived peptide agonist of FGFR1). Like FGF1, FGL induced tyrosine phosphorylation of FGFR1, FRS2alpha, ShcA, and PLCgamma in a time- and dose-dependent manner. However, the activation of FRS2alpha by FGL was significantly lower than the activation by FGF1, indicating a differential signaling profile induced by NCAM compared with the cognate growth factor.
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PMID:The fibroblast growth factor receptor (FGFR) agonist FGF1 and the neural cell adhesion molecule-derived peptide FGL activate FGFR substrate 2alpha differently. 2017 7

The Tec family tyrosine kinase (Itk), is a key component of the TCR signaling pathway. Biochemical studies have shown that Itk activation requires recruitment of Itk to the membrane via its pleckstrin homology domain, phosphorylation of Itk by the Src kinase, Lck, and binding of Itk to the SLP-76/LAT adapter complex. However, the regulation of Itk enzymatic activity by Itk domain interactions is not yet well understood. In this study, we show that full-length Itk self-associates in an intermolecular fashion. Using this information, we have designed an Itk variant that exhibits reduced self-association but maintains normal binding to exogenous ligands via each of its regulatory domains. When expressed in insect cells, the Itk substrate phospholipase Cgamma1 is phosphorylated more efficiently by the Itk variant than by wild-type Itk. Furthermore, expression of the Itk variant in primary murine T cells induced higher ERK activation and increased calcium flux following TCR stimulation compared with that of wild-type Itk. Our results indicate that the Tec kinase Itk is negatively regulated by intermolecular clustering and that disruption of this clustering leads to increased Itk kinase activity following TCR stimulation.
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PMID:Disrupting the intermolecular self-association of Itk enhances T cell signaling. 2023 89

Infection with the obligate bacterial intracellular pathogen Chlamydia trachomatis leads to the sustained activation of the small GTPase RAS and many of its downstream signaling components. In particular, the mitogen-activated protein kinase ERK and the calcium-dependent phospholipase cPLA(2) are activated and are important for the onset of inflammatory responses. In this study we tested if activation of ERK and cPLA(2) occurred as a result of RAS signaling during infection and determined the relative contribution of these signaling components to chlamydial replication and survival. We provide genetic and pharmacological evidence that during infection RAS, ERK, and, to a lesser extent, cPLA(2) activation are uncoupled, suggesting that Chlamydia activates individual components of this signaling pathway in a non-canonical manner. In human cell lines, inhibition of ERK or cPLA(2) signaling did not adversely impact C. trachomatis replication. In contrast, in murine cells, inhibition of ERK and cPLA(2) played a significant protective role against C. trachomatis. We determined that cPLA(2)-deficient murine cells are permissive for C. trachomatis replication because of their impaired expression of beta interferon and the induction of immunity-related GTPases (IRG) important for the containment of intracellular pathogens. Furthermore, the MAPK p38 was primarily responsible for cPLA(2) activation in Chlamydia-infected cells and IRG expression. Overall, these findings define a previously unrecognized role for cPLA(2) in the induction of cell autonomous cellular immunity to Chlamydia and highlight the many non-canonical signaling pathways engaged during infection.
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PMID:cPLA2 regulates the expression of type I interferons and intracellular immunity to Chlamydia trachomatis. 2045 86


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