scholarly journals Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase

2005 ◽  
Vol 25 (8) ◽  
pp. 1551-1557 ◽  
Author(s):  
Thomas Münzel ◽  
Andreas Daiber ◽  
Volker Ullrich ◽  
Alexander Mülsch
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Endothelial Nitric Oxide Synthase ◽  
Soluble Guanylyl Cyclase ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

scholarly journals AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2

2016 ◽  
Vol 36 (24) ◽  
pp. 3086-3099 ◽  
Author(s):  
Kwang-jin Cho ◽  
Darren E. Casteel ◽  
Priyanka Prakash ◽  
Lingxiao Tan ◽  
Dharini van der Hoeven ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Plasma Membrane ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Cyclic Gmp ◽  
Endothelial Nitric Oxide Synthase ◽  
Intact Cells ◽  
Dependent Protein ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

K-Ras must localize to the plasma membrane and be arrayed in nanoclusters for biological activity. We show here that K-Ras is a substrate for cyclic GMP-dependent protein kinases (PKGs). In intact cells, activated PKG2 selectively colocalizes with K-Ras on the plasma membrane and phosphorylates K-Ras at Ser181 in the C-terminal polybasic domain. K-Ras phosphorylation by PKG2 is triggered by activation of AMP-activated protein kinase (AMPK) and requires endothelial nitric oxide synthase and soluble guanylyl cyclase. Phosphorylated K-Ras reorganizes into distinct nanoclusters that retune the signal output. Phosphorylation acutely enhances K-Ras plasma membrane affinity, but phosphorylated K-Ras is progressively lost from the plasma membrane via endocytic recycling. Concordantly, chronic pharmacological activation of AMPK → PKG2 signaling with mitochondrial inhibitors, nitric oxide, or sildenafil inhibits proliferation of K-Ras-positive non-small cell lung cancer cells. The study shows that K-Ras is a target of a metabolic stress-signaling pathway that can be leveraged to inhibit oncogenic K-Ras function.

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