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

Kwang-Jin Cho; Darren E Casteel; Priyanka Prakash; Lingxiao Tan; Dharini van der Hoeven; Angela A Salim; Choel Kim; Robert J Capon; Ernest Lacey; Shane R Cunha; Alemayehu A Gorfe; John F Hancock

doi:10.1128/MCB.00365-16

Back

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

Journal article

Open access

Peer reviewed

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

Kwang-Jin Cho, Darren E Casteel, Priyanka Prakash, Lingxiao Tan, Dharini van der Hoeven, Angela A Salim, Choel Kim, Robert J Capon, Ernest Lacey, Shane R Cunha, …

Molecular and cellular biology, Vol.36(24), pp.3086-3099

12/01/2016

DOI: 10.1128/MCB.00365-16

PMCID: PMC5126295

PMID: 27697864

Files and links (1)

url

https://doi.org/10.1128/MCB.00365-16View

Published (Version of record) Open Access

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.

AMP-Activated Protein Kinases - metabolism

Animals

Carcinoma, Non-Small-Cell Lung - metabolism

Cell Line

Cell Line, Tumor

Cell Membrane - metabolism

Cell Proliferation - drug effects

Cyclic GMP-Dependent Protein Kinase Type II - metabolism

Dogs

Endocytosis

Gene Expression Regulation, Neoplastic

Humans

Lung Neoplasms - metabolism

Madin Darby Canine Kidney Cells

Nitric Oxide - pharmacology

Nitric Oxide Synthase Type III - metabolism

Phosphorylation

ras Proteins - chemistry

ras Proteins - metabolism

Serine - metabolism

Signal Transduction

Sildenafil Citrate - pharmacology

Details

Title: Subtitle: AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2
Creators: Kwang-Jin Cho - The University of Texas Health Science Center at Houston
Darren E Casteel - University of California San Diego
Priyanka Prakash - The University of Texas Health Science Center at Houston
Lingxiao Tan - The University of Texas Health Science Center at Houston
Dharini van der Hoeven - The University of Texas Health Science Center at Houston
Angela A Salim - The University of Queensland
Choel Kim - Baylor College of Medicine
Robert J Capon - The University of Queensland
Ernest Lacey - Microbial Screening Technologies Pty., Ltd., Smithfield, New South Wales, Australia
Shane R Cunha - The University of Texas Health Science Center at Houston
Alemayehu A Gorfe - The University of Texas Health Science Center at Houston
John F Hancock - The University of Texas Health Science Center at Houston
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.36(24), pp.3086-3099
DOI: 10.1128/MCB.00365-16
PMID: 27697864
PMCID: PMC5126295
NLM abbreviation: Mol Cell Biol
ISSN: 1098-5549
eISSN: 1098-5549
Grant note: R01 GM100078 / NIGMS NIH HHS R00 CA188593 / NCI NIH HHS K99 CA188593 / NCI NIH HHS R25 GM056929 / NIGMS NIH HHS
Language: English
Date published: 12/01/2016
Academic Unit: Oral Pathology, Radiology and Medicine; Dentistry Administration
Record Identifier: 9985157463902771

Metrics

1 Record Views