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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sympatho-adrenergic activity and the renin-angiotensin system are considered critical regulators of obesity and hypertension. The novel angiotensin II type 1 receptor-associated protein (ATRAP) has been demonstrated to modulate angiotensin II signalling in smooth muscle cells and cardiomyocytes. Adipose tissue expresses important renin angiotensin system components and contributes to cardiometabolic disease. However, ATRAP expression and regulation in adipocytes are unknown. We investigated expression of this novel modulator of angiotensin signalling and its regulation by beta-adrenergic receptors. We found ATRAP to be expressed in differentiated brown and white adipocytes. Stimulation of beta-adrenoceptors strongly suppressed ATRAP expression. We hypothesised a role for JAK/STAT signalling elements. Indeed, beta3-adrenergic stimulation robustly stimulated both STAT1 and STAT3 phosphorylation in a time- and dose-dependent manner. This effect was abrogated by inhibition of PKA and JAK2 signalling. Moreover, inhibition of JAK/STAT and PKA signalling reversed the beta3-adrenergic suppression of ATRAP expression. This study provides the first evidence for expression and adrenergic regulation of the angiotensin II signalling modulator ATRAP in adipocytes. Further, it indicates a novel regulatory link between beta-adrenergic and JAK/STAT signalling.
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PMID:Expression of ATRAP in adipocytes and negative regulation by beta-adrenergic stimulation of JAK/STAT. 1823 61

The small G protein Rho signaling pathways are recognized as major regulators of cardiovascular functions, and activation of Rho proteins appears to be a common component for the pathogenesis of hypertension and vascular proliferative disorders. Recent evidence suggests that modulation of Rho protein signaling by phosphorylation of Rho proteins provides an additional simple mechanism for coordinating Rho protein functions. Phosphorylation of RhoA by cAMP- or cGMP-activated kinase on Ser188 induces cytosolic sequestration of RhoA through increased interaction with guanine dissociation inhibitor, thereby resulting in inhibition of RhoA-dependent functions. Here we show that stimulation of angiotensin II (Ang II) type 2 receptor (AT(2)R) in vascular smooth muscle cells induces Ser188 phosphorylation of RhoA independently of cAMP- or cGMP-activated kinase. We identify the Ser/Thr kinase Ste20-related kinase SLK as a new kinase phosphorylating RhoA on Ser188. Activation of the signaling cascade involving Src homology 2 domain-containing protein-tyrosine phosphatase 1, casein kinase II and SLK is responsible for RhoA phosphorylation and inhibition of RhoA-mediated arterial contraction induced by AT(2)R activation. These results thus identify the molecular mechanism linking AT(2)R to RhoA inhibition and vasodilation.
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PMID:Ste20-related kinase SLK phosphorylates Ser188 of RhoA to induce vasodilation in response to angiotensin II Type 2 receptor activation. 1849 11

Our laboratories have previously identified the alpha7 nAChR-JAK2 pathway as playing a central role in nicotine-induced neuroprotection. We have also reported that the angiotensin II (Ang II) AT(2) receptor induced activation of SHP-1 induces the tyrosine dephosphorylation of JAK2 that results in a complete neutralization of the alpha7 nAChR-JAK2 pro-survival cascade. In this study, we investigated the effects of inhibiting the alpha7 nAChR-JAK2 pro-survival cascade on the nicotine-induced production of the survival factor Bcl-2 and the transcriptional activation of NF-kappaB, AP-1, STAT1, STAT3, and STAT5. We report that nicotine induced the production of Bcl-2 and increased the transcriptional activation of NF-kappaB, AP-1, STAT1, and STAT3, and with the exception of AP-1, the other transcription factors (NF-kappaB, STAT1, and STAT3) were significantly reduced by JAK2 inhibition. We also demonstrate that, via transfection of either Bcl-2 antisense or NF-kappaB, STAT1 and STAT3 transcription factor decoys oligodeoxyribonucleotides into PC12 cells, nicotine induces its neuroprotection in PC12 cells via activation of the alpha7 nAChR-JAK2-(NF-kappaB; STAT3)-Bcl-2 pro-survival pathway. Finally, the neuroprotective nicotine-induced production of Bcl-2 appears to fully counteract the Abeta (1-42)-induced apoptosis of PC12 cells by blocking Abeta (1-42)-induced mitochondrial release of cytosolic cytochrome C.
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PMID:Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. 1906 68

Aldosterone synthesis is primarily regulated by angiotensin II and potassium ions. In addition, endothelial cell-secreted factors have been shown to regulate mineralocorticoid release. We analyzed the pathways that mediate endothelial cell-factor-induced aldosterone release from adrenocortical cells, NCI-H295R using endothelial cell-conditioned medium (ECM). The cAMP antagonist Rp-cAMP caused a 44% decrease in the ECM-induced aldosterone release but inhibition of cAMP-dependent PKA had no effect on aldosterone release. Interestingly, inhibition of cAMP-regulated guanine nucleotide exchange factor Epac with brefeldin-A decreased the ECM-induced aldosterone release by 45%. Similarly, inhibition of p38 MAP-kinase; PI-3-kinase and PKB significantly reduced the ECM-induced aldosterone release whereas inhibition of ERK1/2 and PKC did not decrease aldosterone release. These results provide evidence for the existence of a cAMP-dependent but PKA-independent pathway in mediating the ECM-induced aldosterone release and the significant influence of more than one signaling mechanism.
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PMID:Endothelial factors mediate aldosterone release via PKA-independent pathways. 1907 32

Peroxisome proliferator-activated receptors delta (PPARdelta) is known to be expressed ubiquitously, and the predominant PPAR subtype of cardiac cells. However, relatively less is known regarding the role of PPARdelta in cardiac cells except that PPARdelta ligand treatment protects cardiac hypertrophy by inhibiting NF-kappaB activation. Thus, in the present study, we examined the effect of selective PPARdelta ligand L-165041 on angiotensin II (AngII) induced cardiac hypertrophy and its underlying mechanism using cardiomyocyte. According to our data, L-165041 (10 microM) inhibited AngII-induced [(3)H] leucine incorporation, induction of the fetal gene atrial natriuretic factor (ANF) and increase of cardiomyocyte size. Previous studies have implicated the activation of focal adhesion kinase (FAK) in the progress of cardiomyocyte hypertrophy. L-165041 pretreatment significantly inhibited AngII-induced intracellular Ca(2+) increase and subsequent phosphorylation of FAK. Further experiment using Ca(2+) ionophore A23187 confirmed that Ca(2+) induced FAK phosphorylation, and this was also blocked by L-165041 pretreatment. In addition, overexpression of PPARdelta using adenovirus significantly inhibited AngII-induced intracellular Ca(2+) increase and FAK expression, while PPARdelta siRNA treatment abolished the effect of L-165041. These data indicate that PPARdelta ligand L-165041 inhibits AngII induced cardiac hypertrophy by suppressing intracellular Ca(2+)/FAK/ERK signaling pathway in a PPARdelta dependent mechanism.
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PMID:PPARdelta activation inhibits angiotensin II induced cardiomyocyte hypertrophy by suppressing intracellular Ca2+ signaling pathway. 1922 36

Matrix metalloproteinases (MMPs) play an important role in the pathogenesis of cardiovascular diseases and are modified in response to a variety of stimuli such as bioactive peptides, cytokines and/or grown factors. In this study, we demonstrated that angiotensin II (Ang II) induces a time- and dose-dependent increase in the activity of metalloproteinase 2 (MMP 2) in human umbilical vein endothelial cells (HUVEC). The effect of Ang II was markedly attenuated in cells pretreated with wortmannin and LY294002, two selective inhibitors of phosphatidylinositol-3-kinase (PI3K), indicating that PI3K plays a key role in regulating MMP 2 activity. Similar results were observed when HUVEC were pretreated with genistein, a non-selective tyrosine kinases inhibitor, or with the specific Src-family tyrosine kinase inhibitor PP2, demonstrating the involvement of protein tyrosine kinases, and particularly Src-family tyrosine kinases on the downstream signaling pathway of Ang II receptors. Furthermore, Ang II-induced MMP 2 activation was markedly blocked by SP600125, a selective c-Jun N-terminal kinase (JNK) inhibitor, or pre-treatment of cells with antisense oligonucleotide to focal adhesion kinase (FAK), indicating that both molecules were important for the activation of MMP 2 by Ang II receptor stimulation. In conclusion, these results suggest that Ang II mediates an increase in MMP 2 activity in macrovascular endothelial cells through signal transduction pathways dependent on PI3K and Src-family tyrosine kinases activation, as well as JNK and FAK phosphorylation.
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PMID:Angiotensin II induces MMP 2 activity via FAK/JNK pathway in human endothelial cells. 1933 50

We have previously demonstrated the presence of active epidermal growth factor receptor (EGFR) and its involvement in sperm capacitation and the acrosome reaction; however, the mechanism of EGFR activation was not clear. We show here that the sperm EGFR can be transactivated by angiotensin II or by lysophosphatydic acid, two ligands which activate specific G-protein-coupled receptors (GPCR), or by directly activating protein kinase A using 8Br-cAMP. This transactivation occurs in noncapacitated sperm and is mediated by PKA, SRC and a metalloproteinase. We also show that the EGFR is activated in sperm incubated under in vitro capacitation conditions, without any added ligand, but not in bicarbonate-deficient medium or when PKA is blocked. Despite the fact that EGFR is activated in capacitated sperm, this state is not sufficient to induce the acrosome reaction. We conclude that the EGFR is stimulated during capacitation via PKA activation, while further activation of the EGFR in capacitated sperm is required in order to induce the acrosome reaction. The acrosome reaction can be induced by GPCR via the transactivation of the EGFR by a signaling pathway involving PKA, SRC and metalloproteinase and the EGFR down-stream effectors PI3K, PLC and PKC.
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PMID:Bovine sperm acrosome reaction induced by G-protein-coupled receptor agonists is mediated by epidermal growth factor receptor transactivation. 1966 15

We have shown that tyrosine kinases and mitogen-activated protein kinases mediate angiotensin II (Ang II) effects in cultured rat astrocytes. In this study, we investigated whether Ang II induces Janus kinase (JAK) 2, signal transducer and activators of transcription (STAT) 3 phosphorylation, and interleukin-6 (IL-6) secretion in cultured brainstem rat astrocytes. Ang II increased JAK2 phosphorylation in a time- and dose-dependent manner. Maximal phosphorylation of 1.7+/-0.4 fold above basal was observed at 15 min with 100 nM Ang II. Losartan (10 microM), an AT(1) receptor blocker, inhibited Ang II-mediated JAK2 phosphorylation, while 10 microM PD123319, an AT(2) receptor blocker, was ineffective. The JAK2 inhibitor, AG490 (50 microM), prevented Ang II JAK2 phosphorylation. Ang II also stimulated STAT3 in a concentration- and time-dependent manner. Maximal phosphorylation of 0.8+/-0.11 above basal was observed at 15 min with 100 nM Ang II. Treatment with AG490 reduced Ang II phosphorylation of STAT3 and Ang II-induced astrocyte growth suggesting that JAK2 is an upstream signal in these Ang II effects. Ang II also stimulated IL-6 secretion from brainstem astrocytes in a concentration- and time-dependent manner. Maximal IL-6 secretion of 0.7+/-0.2 above basal was observed with 100 nM Ang II after 48 h of treatment. Losartan decreased Ang II-induced IL-6 secretion while PD123319 was ineffective. Interestingly, AG490 reduced Ang II-stimulated IL-6 secretion. Our study showed for the first time that Ang II induced JAK2/STAT3 phosphorylation and IL-6 secretion through activation of the Ang II AT(1) receptor in brainstem astrocytes. In addition, Ang II stimulated IL-6 secretion and astrocyte growth through the JAK2 pathway in brainstem astrocytes. These results provide new insights into pro-inflammatory and mitogenic signaling mechanisms of Ang II in astrocytes.
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PMID:Angiotensin II activates JAK2/STAT3 pathway and induces interleukin-6 production in cultured rat brainstem astrocytes. 1974 27

The angiotensin converting enzyme (ACE) catalyzes the extracellular formation of angiotensin II, and degradation of bradykinin, thus regulating blood pressure and renal handling of electrolytes. We have previously shown that exogenously added ACE elicited transcriptional regulation independent of its enzymatic activity. Because transcriptional regulation generates from protein-DNA interactions within the cell nucleus we have investigated the initial cellular response to exogenous ACE and the putative internalization of the enzyme in smooth muscle cells (SMC) and endothelial cells (EC). The following phenomena were observed when ACE was added to cells in culture: 1) it bound to SMC and EC with high affinity (K(d) = 361.5 +/- 60.5 pM) and with a low binding occupancy (B(max) = 335.0 +/- 14.0 molecules/cell); 2) it triggered cellular signaling resulting in late activation of focal adhesion kinase and SHP2; 3) it modulated platelet-derived growth factor receptor-beta signaling; 4) it was endocytosed by SMC and EC; and 5) it transited through the early endosome, partially occupied the late endosome and the lysosome, and was localized to the nuclei. The incorporation of ACE or a fragment of it into the nuclei reached saturation at 120 min, and was preceded by a lag time of 40 min. Internalized ACE was partially cleaved into small fragments. These results revealed that extracellular ACE modulated cell signaling properties, and that SMC and EC have a pathway for delivery of extracellular ACE to the nucleus, most likely involving cell surface receptor(s) and requiring transit through late endosome/lysosome compartments.
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PMID:Cell signaling, internalization, and nuclear localization of the angiotensin converting enzyme in smooth muscle and endothelial cells. 2002 59

A cell-penetrating peptide consisting of the second intracellular loop (IC2) of the angiotensin II (AngII) type-I receptor (AT1) linked to the HIV-transactivating regulatory protein (TAT) domain was used to identify the role of this motif In intracellular signal transduction. HEK-293 cells stably transfected with AT1R cDNA and primary cultures of human pulmonary artery smooth muscle cells expressing endogenous AT1 receptor were exposed to the cell-penetrating peptide construct, and the effect on angiotensin II signaling was determined. The AT1 IC2 peptide effectively inhibited AngII-stimulated phosphatidylinositol turnover and calcium influx. It also limited the activation of Akt/PKB as determined by an inhibition of phosphorylation of Akt at Ser473, and completely abolished the AngII-dependent activation of the transcriptional factor NFkappaB. In contrast, the AT1 IC2 peptide had no effect on AngII/AT1 receptor activation of ERK. These results illustrate the potential of using cell-penetrating peptides to both delineate receptor-mediated signal transduction and to selectively regulate G protein-coupled receptor signaling.
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PMID:Limiting angiotensin II signaling with a cell-penetrating peptide mimicking the second intracellular loop of the angiotensin II type-I receptor. 2049 49


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