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
Mol. Cell. Biol. Mol. Cell. Biol. 2016, 36, 3086-3099.
Publication Date: September 26, 2016
https://doi.org/10.1128/MCB.00365-16
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.
