Macropinocytosis Mechanisms in Cellular Processes
Summary
Macropinocytosis is a conserved mechanism by which eukaryotic cells engulf large volumes of extracellular fluid and macromolecules through actin-driven membrane ruffles that evolve into macropinosomes. Initiated by growth factors or constitutive signalling, it relies on the coordinated activation of small GTPases such as Ras, Rac1 and Cdc42, and localised phosphoinositide turnover to orchestrate ruffle formation, cup closure and vesicle scission. Once internalised, macropinosomes mature through Rab GTPase–mediated trafficking and fuse with lysosomes for cargo degradation and nutrient reclamation. This pathway underpins key physiological processes including antigen presentation, nutrient sensing and receptor trafficking, and its dysregulation is implicated in cancer metabolism, immune surveillance and pathogen entry. Advances in understanding these mechanisms are driving novel therapeutic strategies in oncology and immunology.
Research from Nature Portfolio
Recent studies have shown that extracellular protein aggregation at the cell surface can trigger a macroendocytic uptake route analogous to macropinocytosis, enabling rapid internalisation and lysosomal degradation of aggregated receptors. This actin-driven process operates independently of clathrin and dynamin and can be induced by physical or chemical stress. In another foundational investigation, calcium-sensing receptors were demonstrated to regulate constitutive macropinocytosis in macrophages through a calcium-dependent signalling cascade involving phosphatidylinositol 3-kinase and phospholipase C, thereby promoting ruffle formation and antigen uptake for immune surveillance.
Macropinocytosis Mechanisms in Cellular Processes publication trend
The graph below shows the total number of articles in macropinocytosis mechanisms in cellular processes across all publications each year (not limited to Nature Index journals).
Technical terms
Macropinocytosis: A non-selective endocytic process that internalises extracellular fluid and solutes into large vesicles called macropinosomes.
Macropinosome: A large, actin-coated vesicle formed by the closure of membrane ruffles during macropinocytosis.
Circular dorsal ruffle (CDR): A ring-shaped, actin-driven membrane structure that precedes macropinosome formation.
Rac1: A small GTPase that regulates actin polymerisation and membrane ruffling in macropinocytosis.
Lysophosphatidic acid (LPA): A lipid signalling molecule whose receptor uptake via macropinocytosis can modulate cell migration.
References
- Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis. Nature Communications (2023).
- Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages. Nature Communications (2016).
- Aberrant expression of GTPase-activating protein ARAP1 triggers circular dorsal ruffles associated with malignancy in hepatocellular carcinoma Hep3B cells. Cell Communication and Signaling (2025).
- CYRI-B-mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake. eLife (2024).
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