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)

Endothelin-1 (ET-1) and angiotensin-II (AT-II) participate in the pathophysiology of cardiovascular diseases. Regulation of gap junctional intercellular communication may influence heart function and its response to cardiac injury. In this study, we examined the effects of ET-1 and AT-II on connexin43 (Cx43) and connexin40 (Cx40) in cultured neonatal rat ventricular cardiomyocytes (NRCs) and the role of mitogen-activated protein kinase signaling in the ET-1- and AT-II-induced responses. NRCs were incubated for 24 h with either ET-1 or AT-II (each at concentrations ranging from 10 to 1000 nM), and Cx43 expression and phosphorylation increased with increasing concentrations of both. ET-1 effects were significantly blocked by ETA (BQ123), but not by ETB (BQ788), receptor antagonists. AT-II-induced Cx43 induction could be completely inhibited by the AT1 receptor antagonist losartan. In contrast to Cx43, Cx40 expression did not change in either ET-1- or in AT-II-treated NRCs. Thus, these two connexins were differentially regulated. ET-1 and AT-II increased the gap junctional conductance between the cardiomyocytes in culture as measured using a dual-cell voltage clamp. Mitogen-activated protein kinase inhibition revealed that ERK1/2 was critical for up-regulation of Cx43 in response to ET-1, whereas both ERK and p38 signal pathways were involved in the regulation of Cx43 by AT-II. Thus, stimulation of the ERK and p38 signal pathways via ETA and AT1 receptors may partcipate in the regulation of cardiac gap junctions under (patho)physiological conditions.
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PMID:Chronic effects of endothelin 1 and angiotensin II on gap junctions and intercellular communication in cardiac cells. 1170 93

The agonist-induced internalization of several G protein-coupled receptors is an obligatory requirement for their activation of MAPKs. Studies on the relationship between endocytosis of the angiotensin II (Ang II) type 1 receptor (AT1-R) and Ang II-induced ERK1/2 activation were performed in clone 9 (C9) rat hepatic cells treated with inhibitors of endocytosis [sucrose, phenylarsine oxide (PAO), and concanavalin A]. Although Ang II-induced endocytosis of the AT1-R was prevented by sucrose and PAO, and was partially inhibited by concanavalin A, there was no impairment of Ang II-induced ERK activation. However, the specific epidermal growth factor receptor (EGF-R) kinase inhibitor, AG1478, abolished Ang II-induced activation of ERK1/2. Sucrose and PAO also inhibited EGFinduced internalization of the EGF-R in C9 cells, and the inability of these agents to impair EGF-induced ERK activation suggested that the latter is also independent of receptor endocytosis. In COS-7 cells transiently expressing the rat AT1A-R, Ang II also caused ERK activation through EGF-R transactivation. Furthermore, a mutant AT1A-R with truncated carboxyl terminus and impaired internalization retained full ability to activate ERK1/2 in response to Ang II stimulation. These findings demonstrate that Ang II-induced ERK1/2 activation in C9 hepatocytes is independent of both AT1-R and EGF-R endocytosis and is mediated by transactivation of the EGF-R.
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PMID:Independence of angiotensin II-induced MAP kinase activation from angiotensin type 1 receptor internalization in clone 9 hepatocytes. 1187 20

We investigated the effects of a 3-week treatment with various combinations of angiotensin-converting enzyme inhibitor (ACEI) and B1 and B2 bradykinin receptor (B1R and B2R) antagonists (B1A and B2A) and AT1 receptor antagonist on ERK 1 and 2 phosphorylation in isolated glomeruli from streptozotocin-treated diabetic rats (STZ rats). Body weight, glycemia, and blood pressure were monitored. The rats were divided into nine groups: (1) control; and groups 2-9 were STZ treated with (3) insulin, (4) ACEI, (5) ACEI + B1A, (6) ACEI + B2A, (7) B2A, (8) B1A, (9) AT1 antagonist. ERK 1 and 2 phosphorylation and expression of B1R and B2R were assessed by Western blot analysis. ERK 1 and 2 phosphorylation was higher in STZ rats; this activation was normalized by insulin and reduced by ACEI but not by AT1 antagonist. The reduction of ERK 1 and 2 phosphorylation by the ACEI was reversed by B1A and B2A. The induction of B1R was confirmed by increased expression of mRNA and B1 receptor protein. Since ERK 1 and 2 phosphorylation is an early event in the induction of matrix secretion and hyperproliferation associated with diabetic nephropathy, activation of B1R and B2R appears to be a useful pharmacological target in the management of this pathology.
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PMID:Induction of B1 receptors in streptozotocin diabetic rats: possible involvement in the control of hyperglycemia-induced glomerular Erk 1 and 2 phosphorylation. 1202 68

Angiotensin II (AII) plays an important role in renal proximal tubular acidification via the costimulation of basolateral Na/HCO3 cotransporter (NBC) and apical Na/H exchanger (NHE) activities. These effects are mediated by specific G protein-coupled AII receptors, but their corresponding downstream effectors are incompletely defined. Src family tyrosine kinases (SFKs) contribute to the regulation of both transport activities by a variety of stimuli and are coupled to classic mitogen-activated protein kinase (MAPK) pathway activation in this cell type. We therefore examined these signaling intermediates for involvement in AII-stimulated NBC activity in cultured proximal tubule cells. Subpressor concentrations of AII (0.1 nM) increased NBC activity within minutes, and this effect was abrogated by selective antagonism of AT1 angiotensin receptors, SFKs, or the classic MAPK pathway. AII directly activated Src, as well as the proximal (Raf) and distal (ERK) elements of the classic MAPK module, and the activation of Src was prevented by AT1 receptor antagonism. An associated increase in basolateral membrane NBC1 content is compatible with the involvement of this proximal tubule isoform in these changes. We conclude that AII stimulation of the AT1 receptor increases NBC activity via sequential activation of SFKs and the classic MAPK pathway. Similar requirements for SFK/MAPK coupling in both cholinergic and acidotic costimulation of NBC and NHE activities suggest a central role for these effectors in the coordinated regulation of epithelial transport by diverse stimuli.
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PMID:Angiotensin II stimulation of renal epithelial cell Na/HCO3 cotransport activity: a central role for Src family kinase/classic MAPK pathway coupling. 1202 70

Angiotensin II (Ang II) is a multifunctional hormone that influences the function of cardiovascular cells through a complex series of intracellular signaling events initiated by the interaction of Ang II with AT1 and AT2 receptors. AT1 receptor activation leads to cell growth, vascular contraction, inflammatory responses and salt and water retention, whereas AT2 receptors induce apoptosis, vasodilation and natriuresis. These effects are mediated via complex, interacting signaling pathways involving stimulation of PLC and Ca2+ mobilization; activation of PLD, PLA2, PKC, MAP kinases and NAD(P)H oxidase, and stimulation of gene transcription. In addition, Ang II activates many intracellular tyrosine kinases that play a role in growth signaling and inflammation, such as Src, Pyk2, p130Cas, FAK and JAK/STAT. These events may be direct or indirect via transactivation of tyrosine kinase receptors, including PDGFR, EGFR and IGFR. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of Ang receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways may be pivotal in structural and functional abnormalities that underlie pathological processes in cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis.
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PMID:Recent advances in angiotensin II signaling. 1221 72

Although tyrosine kinases are critically involved in the angiotensin II (Ang II) type 1 (AT1) receptor signaling, how AT1 receptors activate tyrosine kinases is not fully understood. We examined the structural requirements of the AT1 receptor for transactivation of the epidermal growth factor (EGF) receptor (EGFR). Studies using carboxyl terminal-truncated AT1 receptors indicated that the amino acid sequence between 312 and 337 is required for activation of EGFR. The role of the conserved YIPP motif in this sequence in transactivation of EGFR was investigated by mutating tyrosine 319. Ang II failed to activate EGFR in cells expressing AT1-Y319F, whereas EGFR was activated even without Ang II in cells expressing AT1-Y319E, which mimics the AT1 receptor phosphorylated at Tyr-319. Immunoblot analyses using anti-phospho Tyr-319-specific antibody showed that Ang II increased phosphorylation of Tyr-319. EGFR interacted with the AT1 receptor but not with AT1-Y319F in response to Ang II stimulation, whereas the EGFR-AT1 receptor interaction was inhibited in the presence of dominant negative SHP-2. The requirement of Tyr-319 seems specific for EGFR because Ang II-induced activation of other tyrosine kinases, including Src and JAK2, was preserved in cells expressing AT1-Y319F. Extracellular signal-regulated kinase activation was also maintained in AT1-Y319F through activation of Src. Overexpression of wild type AT1 receptor in cardiac fibroblasts enhanced Ang II-induced proliferation. By contrast, overexpression of AT1-Y319F failed to enhance cell proliferation. In summary, Tyr-319 of the AT1 receptor is phosphorylated in response to Ang II and plays a key role in mediating Ang II-induced transactivation of EGFR and cell proliferation, possibly through its interaction with SHP-2 and EGFR.
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PMID:Phosphorylation of tyrosine 319 of the angiotensin II type 1 receptor mediates angiotensin II-induced trans-activation of the epidermal growth factor receptor. 1252 32

Angiotensin II (Ang II) receptor subtype 1, AT1, is expressed by the rat thyroid. A relationship between thyroid function and several components of the renin-angiotensin system has also been established, but the Ang II cellular effects in thyrocytes and its transduction signalling remain undefined. The aim of the present paper was to investigate the modulation of the activity of the Na(+)-K(+)ATPase by Ang II and its intracellular transduction pathway in PC-Cl3 cells, an established epithelial cell line derived from rat thyroid. Here we have demonstrated, by RT-PCR analysis, the expression of mRNA for the Ang II AT1 receptor in PC-Cl3 cells; mRNA for the Ang II AT2 receptor was not detected. Ang II was not able to affect the intracellular Ca(2+) concentration in fura-2-loaded cells, but it stimulated the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-zeta) and -iota (PKC-) isoforms with subsequent phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1 and 2). Translocated atypical PKCs displayed temporally different activations, the activation of PKC-zeta being the fastest. PC-Cl3 cells stimulated with increasing Ang II concentrations showed dose- and time-dependent activation of the Na(+)-K(+)ATPase activity, which paralleled the PKC-zeta translocation time course. Na(+)-K(+)ATPase activity modulation was dependent on PKC activation since the PKC antagonist staurosporine abolished the stimulatory effect of Ang II. The inhibition of the ERK kinases 1 and 2 (MEK1 and 2) by PD098059 (2'-amino-3'-methoxyflavone) failed to block the effect of Ang II on the Na(+)-K(+)ATPase activity. In conclusion, our results suggest that Ang II modulates Na(+)-K(+)ATPase activity in PC-Cl3 cells through the AT1 receptor via activation of atypical PKC-zeta while the Ang II-activated PKC- appears to have other as yet unknown functions.
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PMID:Angiotensin II AT1 receptor stimulates Na+ -K+ATPase activity through a pathway involving PKC-zeta in rat thyroid cells. 1252 32

Vascular endothelial growth factor (VEGF), produced predominantly by endothelial cells, is involved in angiogenesis and mitogenesis. Myofibroblasts (myoFb) are phenotypically transformed fibroblast-like cells found at the site of myocardial infarction. Since myoFb play a role in tissue repair/remodeling at the site of infarction, and express endothelin and angiotensin II (AngII), it was interesting to investigate whether myoFb express VEGF and its receptors de novo, and if the expression is influenced by vasoactive peptides. Primary cultures of myoFb were isolated from 4-week-old adult rat heart infarct were used in this study. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), utilizing primers designed to amplify known isoforms of VEGF revealed expression of two predominant forms, VEGF120 and VEGF164 and northern blot hybridization detected VEGF mRNA of 4.5 kb. VEGF actions are mediated via two major receptors, Flt-1 and KDR, and hence the expression of these receptors was investigated. Flt-1 and KDR expression in myoFb was detected by RT-PCR, RNA transcripts were confirmed by northern blot hybridization while western blot confirmed the presence of VEGF, Flt-1 and KDR proteins in myoFb. In this study AngII upregulated VEGF and Flt-1 expression in myoFb, but not KDR; this was mediated predominantly by AT1-receptor. We report for the first time that cardiac myoFb, isolated from the site of infarction express VEGF, its receptors, Flt-1 and KDR, with modulation of VEGF and Flt-1 expression by AngII. Thus, VEGF may contribute to tissue remodeling and angiogenesis at the site of infarction in an autocrine manner.
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PMID:Cardiac myofibroblasts: a novel source of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. 1267 42

We examined the signalling pathways responsible for the Ang II induction of growth in MCF-7 human breast cancer cells. Ang II in MCF-7 cells induced: (a) the translocation from the cytosol to membrane and nucleus of atypical protein kinase C-zeta (PKC-zeta) but not of PKC-alpha, -delta, - epsilon and -eta; (b) the expression of c-fos mRNA and protein; (c) the phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). All these effects were due to the activation of the Ang II type I receptor (AT1) since they were blocked by the AT1 antagonist losartan. The Ang II-stimulated ERK1/2 phosphorylation was blocked by (a) high doses of staurosporine, inhibitor of PKC-zeta, and by a synthetic myristoylated peptide with sequences based on the endogenous PKC-zeta pseudosubstrate region (zeta-PS); (b) PD098059, a mitogen-activated protein kinase kinase inhibitor (MAPKK/MEK); and, moreover, (c) the inhibitors of phosphoinositide 3-kinases (PI3K), LY294002 and wortmannin, thus indicating that PI3K may act upstream of ERK1/2. The Ang II-evoked c-fos induction was blocked only by high doses of staurosporine and by zeta-PS whilst PD098059, LY294002 and wortmannin were ineffective, thus indicating that c-fos induction is not due to ERK1/2 activity. When the epidermal growth factor-receptor (EGFR) tyrosine kinase activity was inhibited by the use of its inhibitor AG1478, Ang II was still able to induce ERK1/2 phosphorylation and c-fos expression, therefore proving that the transactivation of EGFR was not required for these Ang II effects in MCF-7 cells. The previously reported proliferation of MCF-7 cells induced by Ang II was blocked by PD098059 and by wortmannin in a dose-dependent manner, thereby indicating that in MCF-7 cells the PI3K and ERK pathways mediate the mitogenic signalling of AT1. Our results suggest that in MCF-7 cells Ang II activates multiple signalling pathways involving PKC-zeta, PI3K and MAPK; of these pathways only PKC-zeta appears responsible for the induction of c-fos.
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PMID:PKC-zeta is required for angiotensin II-induced activation of ERK and synthesis of C-FOS in MCF-7 cells. 1294 41

Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The signalling mechanism by which Ang II exerts this effect is not precisely known. Downstream potential targets of Ang II are the extracellular-signal-regulated kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ERK2 via the AT1 receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2 and phospholipase A2 inhibitors blocked Ang II-induced ERK1/ERK2 activation. The antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates ERK1/ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these molecules act as downstream signal transducers of Ang II in the signalling pathway linking the Ang II receptor AT1 to ERK1/ERK2 activation. This pathway involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an important role in Ang II-induced mesangial cell hypertrophy.
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PMID:Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells. 1502 96


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