- Title
- Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase
- Creator
- Michell, Belinda J.; Chen, Zhi-ping; Tiganis, Tony; Stapleton, David; Katsis, Frosa; Power, David A.; Sim, Alistair T.; Kemp, Bruce E.
- Relation
- Journal of Biological Chemistry Vol. 276, Issue 21, p. 17625-17628
- Publisher Link
- http://dx.doi.org/10.1074/jbc.C100122200
- Publisher
- American Society for Biochemistry and Molecular Biology
- Resource Type
- journal article
- Date
- 2001
- Description
- Endothelial nitric-oxide synthase (eNOS) is an important regulatory enzyme in the cardiovascular system catalyzing the production of NO from arginine. Multiple protein kinases including Akt/PKB, cAMP-dependent protein kinase (PKA), and the AMP-activated protein kinase (AMPK) activate eNOS by phosphorylating Ser-1177 in response to various stimuli. During VEGF signaling in endothelial cells, there is a transient increase in Ser-1177 phosphorylation coupled with a decrease in Thr-495 phosphorylation that reverses over 10 min. PKC signaling in endothelial cells inhibits eNOS activity by phosphorylating Thr-495 and dephosphorylating Ser-1177 whereas PKA signaling acts in reverse by increasing phosphorylation of Ser-1177 and dephosphorylation of Thr-495 to activate eNOS. Both phosphatases PP1 and PP2A are associated with eNOS. PP1 is responsible for dephosphorylation of Thr-495 based on its specificity for this site in both eNOS and the corresponding synthetic phosphopeptide whereas PP2A is responsible for dephosphorylation of Ser-1177. Treatment of endothelial cells with calyculin selectively blocks PKA-mediated dephosphorylation of Thr-495 whereas okadaic acid selectively blocks PKC-mediated dephosphorylation of Ser-1177. These results show that regulation of eNOS activity involves coordinated signaling through Ser-1177 and Thr-495 by multiple protein kinases and phosphatases.
- Subject
- endothelial nitric-oxide synthase; phosphorylation
- Identifier
- uon:1215
- Identifier
- http://hdl.handle.net/1959.13/26915
- Identifier
- ISSN:0021-9258
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