Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Negative regulation of mitogenic pathways is a fundamental process that remains poorly characterized. The angiotensin II AT2 receptor is a rare example of a 7-transmembrane domain receptor that negatively cross-talks with receptor tyrosine kinases to inhibit cell growth. In the present study, we report the molecular cloning of a novel protein, ATIP1 (AT2-interacting protein), which interacts with the C-terminal tail of the AT2 receptor, but not with those of other receptors such as angiotensin AT1, bradykinin BK2, and adrenergic beta(2) receptor. ATIP1 defines a family of at least four members that possess the same domain of interaction with the AT2 receptor, contain a large coiled-coil region, and are able to dimerize. Ectopic expression of ATIP1 in eukaryotic cells leads to inhibition of insulin, basic fibroblast growth factor, and epidermal growth factor-induced ERK2 activation and DNA synthesis, and attenuates insulin receptor autophosphorylation, in the same way as the AT2 receptor. The inhibitory effect of ATIP1 requires expression, but not ligand activation, of the AT2 receptor and is further increased in the presence of Ang II, indicating that ATIP1 cooperates with AT2 to transinactivate receptor tyrosine kinases. Our findings therefore identify ATIP1 as a novel early component of growth inhibitory signaling cascade.
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PMID:Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. 1512 6

Stimulation of the angiotensin II (Ang II) type 1 receptor (AT1-R) causes phosphorylation of extracellularly regulated kinases 1 and 2 (ERK1/2) via epidermal growth factor receptor (EGF-R) transactivation-dependent or -independent pathways in Ang II target cells. Here we examined the mechanisms involved in agonist-induced EGF-R transactivation and subsequent ERK1/2 phosphorylation in clone 9 (C9) hepatocytes, which express endogenous AT1-R, and COS-7 and human embryonic kidney (HEK) 293 cells transfected with the AT1-R. Ang II-induced ERK1/2 activation was attenuated by inhibition of Src kinase and of matrix metalloproteinases (MMPs) in C9 and COS-7 cells, but not in HEK 293 cells. Agonist-mediated MMP activation in C9 cells led to shedding of heparin-binding EGF (HB-EGF) and stimulation of ERK1/2 phosphorylation. Blockade of HB-EGF action by neutralizing antibody or its selective inhibitor, CRM197, attenuated ERK1/2 activation by Ang II. Consistent with its agonist action, HB-EGF stimulation of these cells caused marked phosphorylation of the EGF-R and its adapter molecule, Shc, as well as ERK1/2 and its dependent protein, p90 ribosomal S6 kinase, in a manner similar to that elicited by Ang II or EGF. Although the Tyr319 residue of the AT1-R has been proposed to be an essential regulator of EGF-R transactivation, stimulation of wild-type and mutant (Y319F) AT1-R expressed in COS-7 cells caused EGF-R transactivation and subsequent ERK1/2 phosphorylation through release of HB-EGF in a Src-dependent manner. In contrast, the noninvolvement of MMPs in HEK 293 cells, which may reflect the absence of Src activation by Ang II, was associated with lack of transactivation of the EGF-R. These data demonstrate that the individual actions of Ang II on EGF-R transactivation in specific cell types are related to differential involvement of MMP-dependent HB-EGF release.
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PMID:Differential pathways of angiotensin II-induced extracellularly regulated kinase 1/2 phosphorylation in specific cell types: role of heparin-binding epidermal growth factor. 1514 54

Autocrine stimulation and paracrine interaction between coronary smooth muscle cells (cSMC) and endothelial cells (EC) act as regulators of the vascular angiogenesis. Basic fibroblast growth factor (bFGF), its receptor FGF-R1, and coreceptor heparansulfate proteoglycan (HSPG) are important components involved in this angiogenic process. We investigated the influence of angiotensin (Ang) II on this trimolecular bFGF complex, the underlying signaling and the proliferative process in human cSMC. Ang II induces an AT1 receptor-dependent expression of bFGF and also upregulates the FGF-R1 and HSPG expression which is suppressed by losartan, the AT1 receptor blocker. AT1 receptor signaling which is characterized by phosphorylation of p42-mitogen-activated protein kinase (MAPK) is involved in Ang II-induced bFGF, FGF-R1 and HSPG upregulation and DNA synthesis in human cSMC. In contrast, inhibition of the AT2 receptor by PD123,319 has no influence on these Ang II-stimulated and via the MAPK cascade-mediated proangiogenic effects. Finally, our data show that the Ang II-induced DNA synthesis in cSMC is mediated via the bFGF expression. In conclusion, our results suggest that the Ang II-induced angiogenic effects in the vessel wall are supported by the AT1 receptor-stimulated and MAPK pathway-mediated upregulation of the autocrine/paracrine trimolecular bFGF complex in cSMC.
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PMID:Angiotensin AT1 receptor upregulates expression of basic fibroblast growth factor, basic fibroblast growth factor receptor and coreceptor in human coronary smooth muscle cells. 1522 45

Although vascular smooth muscle cells (VSMCs) are widely used in cardiovascular research, their phenotypic change under various culture conditions is problematic to evaluate the experimental results obtained. The levels of angiotensin (Ang) type 1/2 (AT1/AT2) receptors as well as contractile and structural proteins are degraded through culture passages. The present study demonstrated that heparin recovered Ang receptors and differentiation markers, such as desmin, SM-22 and smooth muscle alpha-actin in VSMCs at the ninth passage. Heparin also potenciated Ang II-induced activation for ERK1/2 and p38. These results suggest a potential value of heparin-treated VSMCs as the model for analysis of Ang-mediated signal transduction under physiological condition.
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PMID:Heparin recovers AT1 receptor and its intracellular signal transduction in cultured vascular smooth muscle cells. 1562 Jul 27

Regulator of G protein signaling (RGS) proteins act as GTPase-activating proteins (GAPs) for Galpha subunits and negatively regulate G protein-coupled receptor signaling. Using RGS5 gene-specific RT-PCR, we have identified a novel alternative splicing variant of RGS5 mRNA in human ocular tissues. The alternative splicing of RGS5 mRNA occurred at position +44 (GenBank NM_003617), spliced out 174 bp (+44 to +218 bp) of the coding region, and encoded an RGS5s protein with a 108 amino acid N-terminal deletion. This study is the first to document alternative splicing of an RGS5 gene. We therefore studied RGS5 and RGS5s mRNA distribution in human tissues. In the eye, RGS5s was found to be highly expressed in the ciliary body and trabecular meshwork. It was also expressed in the kidney, brain, spleen, skeletal muscle and small intestine, but was not detectable in the liver, lung, heart. RGS5s was not found in monkey and rat ocular tissues, indicating species specificity for the eye. Comparing the recombinant RGS5 and RGS5s expression in HEK293/EBNA cells, RGS5s was present almost exclusively in the cytosolic fraction, whereas RGS5 was present in both membrane and cytosolic fractions. The data suggest that the N-terminal of RGS5 may be important for protein translocation to the cell membrane. Both RGS5 and RGS5s antagonized the rapid phosphorylation of p44/42 MAP kinase induced by Galphai coupled cannibinoid receptor-1 activation. RGS5, but not RGS5s, inhibited the Ca2+ signaling initiated by activation of Galphaq coupled angiotensin II receptors (AT1) and prostaglandin FP receptors. Cotransfection of RGS5s with RGS5 resulted in the blockade of RGS5 actions with respect to inhibition of the signal transduction initiated by activation of both AT1 and FP receptor, suggesting that RGS5s may contain functional domains that compete with RGS5 in the regulation of the Galphaq coupled AT1 and FP receptors. The unique expression pattern, cellular localization and functions of RGS5s suggest that RGS5s may play a critical role in the regulation of intracellular signaling pathways.
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PMID:Identification of a novel alternative splicing variant of RGS5 mRNA in human ocular tissues. 1567 Jan 59

The detailed mechanism of the effects of extracellular Ca2+ entry blockade on angiotensin II (Ang II) type 1 (AT1) receptor-mediated growth-promoting signals in vascular smooth muscle cells (VSMCs) is not fully understood. Ang II stimulation caused biphasic activation of growth-promoting signals, reaching a peak at 5 to 10 min followed by a decrease and a second peak at around 2 to 4 h. Addition of PD98059 (2'-amino-3'-methoxyflavone), a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor, or AG490 [alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide], a Janus-activated kinase 2 (Jak2) inhibitor, even 4 h after Ang II treatment inhibited [3H]thymidine incorporation. The calcium channel blocker azelnidipine attenuated the later peaks of extracellular signal-regulated kinase (ERK), tyrosine kinase 2, Jak2 activation, and phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. Interestingly, azelnidipine increased rather than decreased the later ERK peaks in cells treated with small interfering RNA against mitogen-activated protein kinase phosphatase-1. Ang II-mediated [3H]thymidine incorporation was inhibited dose dependently by azelnidipine and also by azelnidipine, plus olmesartan, whereas olmesartan or azelnidipine alone at such lower doses did not affect [3H]thymidine incorporation. These data provide new insight into the manner in which calcium channels exert an essential action in the AT1 receptor-mediated growth-promoting actions in VSMCs.
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PMID:Effect of azelnidipine on angiotensin II-mediated growth-promoting signaling in vascular smooth muscle cells. 1569 23

Parathyroid hormone-related protein (PTHrP), a mitogenic factor for renal cells, is overexpressed in acute renal failure (ARF). Recent data support an association between PTHrP and the renin-angiotensin system in the damaged kidney. The effects of angiotensin II (Ang II) inhibitors (quinapril, enalapril, and/or losartan) on PTHrP and the PTH1 receptor (PTH1R) expression in rats with either folic acid (FA)- or gentamicin-induced ARF were analyzed. The decreased renal function and the PTHrP upregulation and PTH1R downregulation induced by the nephrotoxins were inhibited by the Ang II blockers. In tubuloepithelial cells NRK-52E, the rapid (10 min) increase in PTHrP mRNA by FA, associated with a perinuclear relocalization of Ang II/AT1 receptor, was inhibited by losartan but not candesartan, which traps Ang II receptors at the cell surface. Maximal PTHrP protein overexpression by FA (at 24 to 72 h)-or by exogenous Ang II-was abolished by both Ang II antagonists. PTHrP upregulation by FA was preceded by increased extracellular signal-regulated kinase (ERK) phosphorylation and inhibited by the ERK inhibitor PD098059. FA also activated cAMP response element-binding (CREB) protein, and this was prevented by losartan in these cells. Moreover, PTHrP mRNA overexpression by either FA or Ang II occurred in NRK 52E that were transfected with a CREB construct but not the dominant-negative CREB133 construct. These findings demonstrate that the decreased renal function and PTHrP overexpression in nephrotoxin-damaged kidney depends on renin-angiotensin system. In this setting, intracellular Ang II/AT1 receptor recycling seems to be related to PTHrP induction through ERK and CREB activation in tubuloepithelial cells.
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PMID:Role of the renin-angiotensin system on the parathyroid hormone-related protein overexpression induced by nephrotoxic acute renal failure in the rat. 1572 88

The properties of urotensin II (U-II) receptor (UT receptor) and angiotensin II (ANG II) receptor (AT receptor) in primary human skeletal myoblasts (HSMM) and differentiated skeletal myotubes (HSMMT) were characterized. Radiolabeled U-II and ANG II bound specifically to HSMM with Kd's of 0.31 nM (2311 receptors/cell) and 0.61 nM (18,257 receptors/cell), respectively. The cyclic segment of U-II peptide, CFWKYC, was the minimal sequence required for binding, with the WKY residues essential. Inhibitor studies suggested AT1 is the predominant ANG II receptor. After radioligand binding, under conditions designed to minimize receptor internalization, half the bound U-II was resistant to acid washing suggesting that U-II binds tightly to its receptor in a quasi-irreversible fashion. The AT1 receptor-bound radioligand was completely removed under the same conditions. RT-PCR detected the expression of mRNAs for UT and AT1 receptors. Western blotting showed that U-II and ANG II signaled via ERK1/2 kinase. UT receptor was not lost upon differentiation into myotubes since both mRNA for UT receptor and U-II binding were still present. ANG II receptors were also present as shown by ANG II-induced calcium mobilization.
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PMID:Characterization of functional urotensin II receptors in human skeletal muscle myoblasts: comparison with angiotensin II receptors. 1575 84

Multiple signaling pathways link the angiotensin II (Ang II) type 1 (AT1) receptor to Gq-dependent inositol phosphate (IP) production and Gq-independent phospho-extracellular signal-activated kinase (p-ERK) 1/2 activation by Ang II in the regulation of cardiovascular vasoconstriction and cell growth, respectively. An Ang II analogue, [Sar1, Ile4, Ile8]Ang II, did not stimulate Gq-dependent IP production, but still activated Gq-independent p-ERK1/2 in human coronary artery smooth muscle cells as well as in a cell line that stably expressed AT1. This activation was mostly mediated by [Sar1, Ile4, Ile8]Ang II-induced Gq-independent epidermal growth factor receptor transactivation. We found that AT1 receptor signaling shows bifurcation into functionally separate pathways. A clear understanding of this unique signaling may be necessary for the development of therapeutic agents to treat disorders such as hypertension and cardiac hypertrophy.
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PMID:Activation of extracellular signal-activated kinase by angiotensin II-induced Gq-independent epidermal growth factor receptor transactivation. 1578 12


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