Figure 1.
Schematic representation of extracellular protein uptake via macropinocytosis in cancer cells. Ras activation, either by growth factor stimulation or through oncogenic mutation, leads to increased membrane ruffling and macropinocytosis via activation of Rac1 and Cdc42, which in turn stimulate p21-activated kinase 1 (Pak1) to induce actin polymerization. Activation of Rac1 and Cdc42 is sensitive to changes in submembranous pH, and the activity of Na+/H+ exchangers (NHEs) and vacuolar H+-ATPase (V-ATPases) is crucial to maintaining pH homeostasis. Conversion of membrane phosphoinositides by PI3-kinase (PI3K) is also necessary for macropinocytosis. Macropinosomes containing extracellular proteins such as albumin and collagen are internalized and subsequently fuse with lysosomes. Lysosomal proteases (▲) allow the catabolism of extracellular proteins into free amino acids (a.a.) that can fuel the TCA cycle to promote cell growth and survival. mTORC1 finely regulates the utilization of extracellular protein-derived amino acids by inhibiting macropinocytosed protein catabolism when free a.a. are abundant. Yellow stars represent phosphorylation of growth factor receptors.