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Mol Cell Biol. 2016 Nov 28;36(24):3086-3099. Print 2016 Dec 15.

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

Author information

1
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Medical School, Houston, Texas, USA.
2
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
3
Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center at Houston, School of Dentistry, Houston, Texas, USA.
4
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
5
Department of Pharmacology, Baylor College of Medicine, Houston, Texas, USA.
6
Microbial Screening Technologies Pty., Ltd., Smithfield, New South Wales, Australia.
7
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Medical School, Houston, Texas, USA john.f.hancock@uth.tmc.edu.

Abstract

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.

PMID:
27697864
PMCID:
PMC5126295
DOI:
10.1128/MCB.00365-16
[Indexed for MEDLINE]
Free PMC Article

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