AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2.
Mol Cell Biol
; 36(24): 3086-3099, 2016 12 15.
Article
en En
| MEDLINE
| ID: mdl-27697864
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 â 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Membrana Celular
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Carcinoma de Pulmón de Células no Pequeñas
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Proteínas ras
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Óxido Nítrico Sintasa de Tipo III
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Proteínas Quinasas Activadas por AMP
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Proteína Quinasa Dependiente de GMP Cíclico Tipo II
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Neoplasias Pulmonares
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Cell Biol
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos