Reactive Oxygen Species Induce Tyrosine Phosphorylation of and Src Kinase Recruitment to NO-sensitive Guanylyl Cyclase

Meurer, Sabine; Pioch, Sylke; Gross, Steffen; Müller‐Esterl, Werner

doi:10.1074/jbc.m507565200

Cited by 46 publications

(27 citation statements)

References 48 publications

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“…However, the mechanism by which SHP-1 regulates sGC activity remains to be studied. Tyrosine kinase phosphorylation of sGC by a Src like kinase in response to H 2 O 2 or pervanadate was reported recently [80]. The physiological implication of such a process remains unknown.…”

Section: Regulation Of Sgc Expression and Activitymentioning

confidence: 96%

NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells

Madhusoodanan

Murad

2006

Neurochem Res

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Nitric oxide (NO) is a short lived diatomic free radical species synthesized by nitric oxide synthases (NOS). The physiological roles of NO depend on its local concentrations as well as availability and the nature of downstream target molecules. At low nanomolar concentrations, activation of soluble guanylyl cyclase (sGC) is the major event initiated by NO. The resulting elevation in the intracellular cyclic GMP (cGMP) levels serves as signals for regulating diverse cellular and physiological processes. The participation of NO and cGMP in diverse physiological processes is made possible through cell type specific spatio-temporal regulation of NO and cGMP synthesis and signal diversity downstream of cGMP achieved through specific target selection. Thus cyclic GMP directly regulates the activities of its downstream effectors such as Protein Kinase G (PKG), Cyclic Nucleotide Gated channels (CNG) and Cyclic nucleotide phosphodiesterases, which in turn regulate the activities of a number of proteins that are involved in regulating diverse cellular and physiological processes. Localization and activity of the NO-cGMP signaling pathway components are regulated by G-protein coupled receptors, receptor and non receptor tyrosine kinases, phosphatases and other signaling molecules. NO also serves as a powerful paracrine factor. At micromolar concentrations, NO reacts with superoxide anion to form reactive peroxinitrite, thereby leading to the oxidation of important cellular proteins. Extensive research efforts over the past two decades have shown that NO is an important modulator of axon outgrowth and guidance, synaptic plasticity, neural precursor proliferation as well as neuronal survival. Excessive NO production as that evoked by inflammatory signals has been identified as one of the major causative reasons for the pathogenesis of a number of neurodegenerative diseases such as ALS, Alzheimers and Parkinson diseases. Regenerative therapies involving transplantation of embryonic stem cells (ES cells) and ES cell derived lineage committed neural precursor cells have recently shown promising results in animal models of Parkinson disease (PD). Recent studies from our laboratory have shown that a functional NO-cGMP signaling system is operative early during the differentiation of embryonic stem cells. The cell type specific, spatio-temporally regulated NO-cGMP signaling pathways are well suited for inductive signals to use them for important cell fate decision making and lineage commitment processes. We believe that manipulating the NO-cGMP signaling system will be an important tool for large scale generation of lineage committed precursor cells to be used for regenerative therapies.

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Section: Regulation Of Sgc Expression and Activitymentioning

confidence: 96%

NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells

Madhusoodanan

Murad

2006

Neurochem Res

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“…5B). Addition of cGMP to the assay did not increase the catalytic activity of PDE2A (data not shown), indicating that the enzyme was fully saturated with cGMP because of the high cytosolic cGMP concentration in COS-1 cells (ϳ10 M) (22) and the high binding affinity of PDE2A for cGMP (IC 50 ϭ 22 nM) (8). Next, we measured PDE activities in the absence and presence of XAP2.…”

Section: The Gaf-a Domain (Gaf-a) the Amino Terminus And Both Gaf Dmentioning

confidence: 99%

Phosphodiesterase 2A Forms a Complex with the Co-chaperone XAP2 and Regulates Nuclear Translocation of the Aryl Hydrocarbon Receptor

Oliveira

Hoffmeister

Gambaryan

et al. 2007

Journal of Biological Chemistry

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100

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Phosphodiesterase type 2A (PDE2A) hydrolyzes cyclic nucleotides cAMP and cGMP, thus efficiently controlling cNMP-dependent signaling pathways. PDE2A is composed of an amino-terminal region, two regulatory GAF domains, and a catalytic domain. Cyclic nucleotide hydrolysis is known to be activated by cGMP binding to GAF-B; however, other mechanisms may operate to fine-tune local cyclic nucleotide levels. In a yeast two-hybrid screening we identified XAP2, a crucial component of the aryl hydrocarbon receptor (AhR) complex, as a major PDE2A-interacting protein. We mapped the XAP2 binding site to the GAF-B domain of PDE2A. PDE assays with purified proteins showed that XAP2 binding does not change the enzymatic activity of PDE2A. To analyze whether PDE2A could affect the function of XAP2, we studied nuclear translocation of AhR, i.e. the master transcription factor controlling the expression of multiple detoxification genes. Notably, regulation of AhR target gene expression is initiated by tetrachlorodibenzodioxin (TCDD) binding to AhR and by a poorly understood cAMP-dependent pathway followed by the translocation of AhR from the cytosol into the nucleus. Binding of PDE2A to XAP2 inhibited TCDD-and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes. Furthermore, PDE2A attenuated TCDD-induced transcription in reporter gene assays. We conclude that XAP2 targets PDE2A to the AhR complex, thereby restricting AhR mobility, possibly by a local reduction of cAMP levels. Our results provide first insights into the elusive cAMP-dependent regulation of AhR.

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“…Desensitization of sGC itself has been reported in various cell types and tissues after exposure to NO (8-11) but its mechanism is unknown. Ser/Thr phosphorylation was proposed to be involved but evidence is still lacking (12), and Tyr phosphorylation was ruled out recently (13). Elucidating the mechanism of sGC desensitization is crucial considering its likely involvement in NO tolerance during the development of oxidative vascular pathophysiologies, atherosclerosis, and pulmonary hypertension.…”

mentioning

confidence: 99%

Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation

Sayed

Baskaran

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

200

129

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The molecular mechanism of desensitization of soluble guanylyl cyclase (sGC), the NO receptor, has long remained unresolved. Posttranslational modification and redox state have been postulated to affect sGC sensitivity to NO but evidence has been lacking. We now show that sGC can be S-nitrosylated in primary aortic smooth muscle cells by S-nitrosocysteine (CSNO), an S-nitrosylating agent, in human umbilical vein endothelial cells after vascular endothelial growth factor treatment and in isolated aorta after sustained exposure to acetylcholine. Importantly, we show that S-nitrosylation of sGC results in decreased responsiveness to NO characterized by loss of NO-stimulated sGC activity. Desensitization of sGC is concentration-and time-dependent on exposure to CSNO, and sensitivity of sGC to NO can be restored and its S-nitrosylation prevented with cellular increase of thiols. We confirm in vitro with semipurified sGC that S-nitrosylation directly causes desensitization, suggesting that other cellular factors are not required. Two potential S-nitrosylated cysteines in the ␣-and ␤-subunits of sGC were identified by MS. Replacement of these cysteines, C243 in ␣ and C122 in ␤, created mutants that were mostly resistant to desensitization. Structural analysis of the region near ␤-C122 in the homologous Nostoc H-NOX crystal structure indicates that this residue is in the vicinity of the heme and its S-nitrosylation could dampen NO activation by affecting the positions of key residues interacting with the heme. This study suggests that S-nitrosylation of sGC is a means by which memory of NO exposure is kept in smooth muscle cells and could be a mechanism of NO tolerance.cGMP ͉ tolerance ͉ redox ͉ S-nitrosothiols I n the cardiovascular system, nitric oxide (NO) is critical for regulation of vascular tone and homeostasis (1, 2). In mammals, the main sensor of NO is the soluble guanylyl cyclase (sGC), a heme-containing heterodimer formed by an ␣-and a ␤-subunit. When NO binds to the heme, catalytic activity of sGC increases several hundredfold to produce the second messenger cGMP (3). Despite the importance of the NO-cGMP pathway in the biology and pathology of the cardiovascular and neuronal systems, modulation of sGC is poorly understood (4, 5). In particular, the mechanism of desensitization of sGC has remained unresolved despite 30 years of effort. Desensitization is the transition to a state in which sGC's response to a new NO stimulation is reduced or abolished. This direct effect on sGC differs from the desensitization of the NO-cGMP pathway caused by decrease in cGMP levels [e.g., because of increased phosphodiesterase activity (6)] or decrease in NO availability (7). Desensitization of sGC itself has been reported in various cell types and tissues after exposure to NO (8-11) but its mechanism is unknown. Ser/Thr phosphorylation was proposed to be involved but evidence is still lacking (12), and Tyr phosphorylation was ruled out recently (13). Elucidating the mechanism of sGC desensitization is crucial considering i...

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Reactive Oxygen Species Induce Tyrosine Phosphorylation of and Src Kinase Recruitment to NO-sensitive Guanylyl Cyclase

Cited by 46 publications

References 48 publications

NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells

NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells

Phosphodiesterase 2A Forms a Complex with the Co-chaperone XAP2 and Regulates Nuclear Translocation of the Aryl Hydrocarbon Receptor

Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation

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