Plasma membrane v-ATPase controls oncogenic Ras-induced macropinocytosis

Oncogenic activation of Ras is associated with the acquisition of a unique set of metabolic dependencies that contribute to tumor cell fitness. Mutant Ras cells are endowed with the capability to internalize and degrade extracellular protein via a fluid–phase uptake mechanism termed macropinocytosis(1). There is a growing appreciation for the role of this Ras-dependent process in the generation of free amino acids that can be used to support tumor cell growth under nutrient limiting conditions(2). 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 (PM) via a pathway that requires protein kinase A (PKA) activation by a bicarbonate-dependent soluble adenylate cyclase (sAC). PM accumulation of v-ATPase is necessary for the cholesterol-dependent association of Rac1 with the PM, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. These observations identify a link between v-ATPase trafficking and nutrient supply by macropinocytosis that could be exploited to curtail the metabolic adaptation capacity of mutant Ras tumor cells.