Metabolic functions of macropinocytosis

Abstract

Macropinocytosis is an evolutionarily conserved form of endocytosis that mediates non-selective uptake of extracellular fluid and the solutes contained therein. In mammalian cells, macropinocytosis is initiated by growth factor-mediated activation of the Ras and PI3-kinase signalling pathways. In malignant cells, oncogenic activation of growth factor signalling sustains macropinocytosis cell autonomously. Recent studies of cancer metabolism, discussed here, have begun to define a role for macropinocytosis as a nutrient uptake route. Macropinocytic cancer cells ingest macromolecules in bulk and break them down in the lysosome to support metabolism and macromolecular synthesis. Thereby, macropinocytosis allows cells to tap into the copious nutrient stores of extracellular macromolecules when canonical nutrients are scarce. These findings demonstrate that macropinocytosis promotes metabolic flexibility and resilience, which enables cancer cells to survive and grow in nutrient-poor environments. Implications for physiological roles of growth factor-stimulated macropinocytosis in cell metabolism and its relationship with other nutrient uptake pathways are considered. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.

Keywords: cancer metabolism; growth factors; lysosome; mTORC1; macropinocytosis; nutrients.

Figure 1.

Nutrient uptake strategies of eukaryotic cells. Unicellular eukaryotes such as the amoeba Dictyostelium discoideum feed by ingesting macromolecular nutrients and bacteria through macropinocytosis or the related phagocytosis. Subsequently, the macromolecular foodstuff is broken down in the lysosome to generate an intracellular nutrient source. Mammalian cells usually reside in an environment that provides ample amino acids and saccharides, which cells import through plasma membrane nutrient transporters. However, macropinocytosis and the endolysosomal system are conserved in mammalian cells and have emerged as a pathway to access the nutritional content of extracellular macromolecules.

Figure 2.

Metabolic benefits of macropinocytosis. (a) Biomass composition of human plasma. Of note, most biomass in circulation is contained within proteins. (b) Macropinocytosis internalizes nutrients according to their extracellular concentration. Proteins are a major cargo of macropinosomes and supply amino acids, and possibly bound lipids, sugar residues and micronutrients. Cellular debris, which is abundant in some pathological contexts, can also be ingested through macropinocytosis.

Figure 3.

Regulation of macropinocytosis. Macropinocytosis is controlled by growth factor signalling. Growth factors activate their cognate receptor tyrosine kinases (RTKs), which through their effectors Ras and PI3-kinase orchestrate actin-driven membrane ruffling and macropinosome formation. Oncogenic mutations that constitutively activate the Ras and PI3-kinase signalling pathways trigger macropinocytosis cell autonomously. Macropinocytosis and lysosomal catabolism of extracellular proteins is also regulated by the cellular metabolic state. Energy depletion leads to activation of AMPK, which in some contexts promotes macropinocytosis induction. Amino acid depletion leads to the inactivation of mTORC1, which enhances lysosomal catabolism of macropinocytosed proteins.

Figure 4.

Macropinocytosis and other nutrient uptake pathways. Nutrient transporters and endocytic receptors mediate selective uptake of dedicated nutrients such as glucose, amino acids and lipoproteins. Macropinocytosis allows cells to access non-dedicated nutrient stores of extracellular macromolecules, with a possible contribution from constitutive pinocytosis. Autophagy has an analogous role in mediating breakdown of intracellular macromolecules as non-dedicated nutrients.