Shaping cups into phagosomes and macropinosomes

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Abstract
Phagocytosis is the ingestion by cells of particles or other cells. Receptors in membranes of phagocytic cells organize the advance of the plasma membrane and the actin cytoskeleton around target particles, forming intracellular membrane-bounded compartments called phagosomes. Macropinocytosis is the ingestion by cells of extracellular solutes and fluid into 0.2–10-μm diameter vesicles, or macropinosomes. Macropinosomes can form spontaneously or in response to activation of cell-surface receptors. Common signalling mechanisms organize the construction of phagocytic or macropinocytic cup-shaped invaginations of the plasma membrane. Receptors, GTPases of the Ras superfamily and membrane phospholipids regulate the component activities of actin-filament assembly, disassembly and contraction, as well as the fusion of membrane vesicles with cup membranes. Imaging of molecular dynamics in living cells indicates that phagocytic and macropinocytic cups exhibit distinct patterns of signalling that correspond to the early and late stages of their formation. Activated receptor complexes (short-range signals) generate diffusible signal molecules (medium-range signals) that are subject to feedback regulation and that, at suprathreshold concentrations, can activate transitions from early to late stages of signalling. Phospholipids generated in the confines of a forming cup integrate and amplify signalling in that region of the membrane. Receptor-mediated signal transduction for phagocytosis and macropinocytosis is modulated by cell structure and is conditional on feedback regulation that is related to cup integrity, particle stiffness and particle shape.