Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis

Nature. 2019 Dec;576(7787):477-481. doi: 10.1038/s41586-019-1831-x. Epub 2019 Dec 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bicarbonates / metabolism
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Membrane / enzymology*
  • Cell Membrane / metabolism
  • Cholesterol / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oncogene Protein p21(ras) / metabolism*
  • Pinocytosis*
  • Signal Transduction
  • Sodium-Bicarbonate Symporters / metabolism
  • Vacuolar Proton-Translocating ATPases / metabolism*


  • Bicarbonates
  • SLC4A7 protein, human
  • Sodium-Bicarbonate Symporters
  • Cholesterol
  • Cyclic AMP-Dependent Protein Kinases
  • Vacuolar Proton-Translocating ATPases
  • Oncogene Protein p21(ras)