Macropinocytosis Signaling

Different mechanisms are available for the endocytic internalization of a variety of particles (Eg molecules, viruses, bacteria), including clathrin-mediated endocytosis, caveolar endocytosis, macropinocytosis and non-clathrin, non-caveolae endocytosis. Macropinocytosis refers to the actin-dependent formation of large endocytic vesicles of irregular size and shape called macropinosomes. This process involves an extensive plasma membrane reorganization and internalization of large quantities of extracellular fluid. Macropinocytosis depends on signaling to the actin cytoskeleton and therefore is highly dependent on the activity of Rho family members, Rac1, RhoA and Cdc42, and their upstream effectors such as Ras and PI3K. Src, PLCγ, and PKC are also involved in the extensive actin rearrangement, which leads to membrane ruffling and formation of macropinosomes. Two types of macropinosomes can be generated, the recycling macropinosomes and the processive macropinosomes. Recycling macropinosmes are formed upon binding of ligands such as EGF, PDGF, NGF and Insulin to Receptor Tyrosine Kinase (RTK), the vesicles travel then into the cytosol, where their content is released or the macropinosomes are recycled back to the cell surface, where their content is released into the extracellular space. The processive macropinosomes are triggered by diverse receptors, including Integrins, the mannose receptor MRC1 or the lipopolysaccharide receptor CD14 and are involved in the uptake of antigen, bacteria, viruses, and apoptotic cells. The processive macropinosomes shrink in size and fuse with late endosomes and lysosomes.