Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis

Craig Ramirez, Andrew D. Hauser, Emily A. Vucic and Dafna Bar-Sagi ()
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Craig Ramirez: New York University School of Medicine
Andrew D. Hauser: New York University School of Medicine
Emily A. Vucic: New York University School of Medicine
Dafna Bar-Sagi: New York University School of Medicine

Nature, 2019, vol. 576, issue 7787, 477-481

Abstract: Abstract Oncogenic activation of RAS is associated with the acquisition of a unique set of metabolic dependencies that contribute to tumour cell fitness. Cells that express oncogenic RAS are able to internalize and degrade extracellular protein via a fluid-phase uptake mechanism termed macropinocytosis1. There is increasing recognition of the role of this RAS-dependent process in the generation of free amino acids that can be used to support tumour cell growth under nutrient-limiting conditions2. However, little is known about the molecular steps that mediate the induction of macropinocytosis by oncogenic RAS. Here we identify vacuolar ATPase (V-ATPase) as an essential regulator of RAS-induced macropinocytosis. Oncogenic RAS promotes the translocation of V-ATPase from intracellular membranes to the plasma membrane via a pathway that requires the activation of protein kinase A by a bicarbonate-dependent soluble adenylate cyclase. Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. These observations establish a link between V-ATPase trafficking and nutrient supply by macropinocytosis that could be exploited to curtail the metabolic adaptation capacity of RAS-mutant tumour cells.

Date: 2019
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DOI: 10.1038/s41586-019-1831-x

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