Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of angiotensin II (Ang II)-induced superoxide production was investigated with HEK293 or Chinese hamster ovary cells reconstituted with the angiotensin type 1 receptor (AT(1)R) and NADPH oxidase (either Nox1 or Nox2) along with a pair of adaptor subunits (either NOXO1 with NOXA1 or p47(phox) with p67(phox)). Ang II enhanced the activity of both Nox1 and Nox2 supported by either adaptor pair, with more effective activation of Nox1 in the presence of NOXO1 and NOXA1 and of Nox2 in the presence of p47(phox) and p67(phox). Expression of several AT(1)R mutants showed that interaction of the receptor with G proteins but not that with beta-arrestin or with other proteins (Jak2, phospholipase C-gamma1, SH2 domain-containing phosphatase 2) that bind to the COOH-terminal region of AT(1)R, was necessary for Ang II-induced superoxide production. The effects of constitutively active alpha subunits of G proteins and of various pharmacological agents implicated signaling by a pathway comprising AT(1)R, Galpha(q/11), phospholipase C-beta, and protein kinase C as largely, but not exclusively, responsible for Ang II-induced activation of Nox1 and Nox2 in the reconstituted cells. A contribution of Galpha(12/13), phospholipase D, and phosphatidyl-inositol 3-kinase to Ang II-induced superoxide generation was also suggested, whereas Src and the epidermal growth factor receptor did not appear to participate in this effect of Ang II. In reconstituted cells stimulated with Ang II, Nox2 exhibited a more sensitive response than Nox1 to the perturbation of protein kinase C, phosphatidylinositol 3-kinase, or the small GTPase Rac1.
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PMID:Mechanism of angiotensin II-induced superoxide production in cells reconstituted with angiotensin type 1 receptor and the components of NADPH oxidase. 1798 2

Glycogen synthase kinase-3beta (GSK-3beta)-modulated IFN-gamma-induced inflammation has been reported; however, the mechanism that activates GSK-3beta and the effects of activation remain unclear. Inhibiting GSK-3beta decreased IFN-gamma-induced inflammation. IFN-gamma treatment rapidly activated GSK-3beta via neutral sphingomyelinase- and okadaic acid-sensitive phosphatase-regulated dephosphorylation at Ser(9), and proline-rich tyrosine kinase 2 (Pyk2)-regulated phosphorylation at Tyr(216). Pyk2 was activated through phosphatidylcholine-specific phospholipase C (PC-PLC)-, protein kinase C (PKC)-, and Src-regulated pathways. The activation of PC-PLC, Pyk2, and GSK-3beta was potentially regulated by IFN-gamma receptor 2-associated Jak2, but it was independent of IFN-gamma receptor 1. Furthermore, Jak2/PC-PLC/PKC/cytosolic phospholipase A(2) positively regulated neutral sphingomyelinase. Inhibiting GSK-3beta activated Src homology-2 domain-containing phosphatase 2 (SHP2), thereby preventing STAT1 activation in the late stage of IFN-gamma stimulation. All these results showed that activated GSK-3beta synergistically affected IFN-gamma-induced STAT1 activation by inhibiting SHP2.
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PMID:Glycogen synthase kinase-3beta facilitates IFN-gamma-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2. 1954 64

Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified nonselective cation current. Therefore, we sought to identify the conductance activated by leptin using whole-cell recording in EGFP-POMC neurons from transgenic mice. The TRPC channel blockers SKF96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride), flufenamic acid, and 2-APB (2-aminoethyl diphenylborinate) potently inhibited the leptin-induced current. Also, lanthanum (La(3+)) and intracellular Ca(2+) potentiated the effects of leptin. Moreover, the diacylglycerol-permeable analog OAG (2-acetyl-1-oleoyl-sn-glycerol) failed to activate any TRPC current. Using a Cs(+)-gluconate-based internal solution, the leptin-activated current reversed near -20 mV. After replacement of external Na(+) and K(+) with Cs(+), the reversal shifted to near 0 mV, and the I/V curve exhibited a negative slope conductance at voltages more negative than -40 mV. Based on scRT-PCR, TRPC1 and TRPC4-7 mRNA were expressed in POMC neurons, with TRPC5 being the most prevalent. The leptin-induced current was blocked by the Jak2 inhibitor AG490, the PI3 kinase inhibitor wortmannin, and the phospholipase C inhibitors, U73122 and ET-18-OCH3. Notably, we identified PLCgamma1 transcripts in the majority of POMC neurons. Therefore, leptin through a Jak2-PI3 kinase-PLCgamma pathway activates TRPC channels, and TRPC1, 4, and 5 appear to be the key channels mediating the depolarizing effects of leptin in POMC neurons.
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PMID:Leptin excites proopiomelanocortin neurons via activation of TRPC channels. 2010 83

Atherosclerosis is a pro-inflammatory condition underlying many cardiovascular diseases. Platelet-activating factor (PAF) and interleukin 6 (IL-6) are actively involved in the onset and progression of atherosclerotic plaques. The involvement of monocyte-derived macrophages is well characterized in the installation of inflammatory conditions in the plaque, but less is known about the contribution of monocyte-derived dendritic cells (Mo-DCs). In the same way, the involvement of calcium, phospholipase C and A2 in PAF-induced IL-6 production, in different cells types, has been shown; however, the importance of the Jak/STAT pathway and its regulation by protein-tyrosine phosphatases in this response have not been addressed. In this study, we report that PAF stimulates PTP1B activity via Jak2, thereby modulating PAF-induced IL-6 production. Using HEK 293 cells stably transfected with the PAF receptor in order to discriminate the pathway components, our results suggest that Jak2 modulates PAF-induced IL-6 production via both positive and negative pathways. Jak2 kinase activity was necessary for maximal transactivation of the IL-6 promoter, as seen by luciferase assays, whereas the same kinase also downregulated this promoter transactivation through the activation of a calcium/calpain/PTP1B pathway. The same pathways were operational in monocyte-derived dendritic cells, since PAF-induced PTP1B activation negatively regulated PAF-induced IL-6 mRNA production and, in addition, Jak2 activated calpain, one of the components involved in PAF-induced PTP1B activation. Results obtained in this study indicate that Jak2 activation is important for maximal IL-6 promoter transactivation by PAF and that PTP1B is involved in the negative regulation of this transactivation. However, PTP1B does not directly regulate Jak2 activation, but rather Jak2 regulates PAF-induced PTP1B activation.
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PMID:Regulation of platelet-activating factor-mediated protein tyrosine phosphatase 1B activation by a Janus kinase 2/calpain pathway. 2868 28


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