Mechanisms of raft clustering. (a) Rafts (red) are small at the plasma membrane, containing only a subset of proteins. (b) Raft size is increased by clustering, leading to a new mixture of molecules. This clustering can be triggered (1) at the extracellular side by ligands, antibodies, or lectins, (2) within the membrane by oligomerization, or (3) by cytosolic agents (cytoskeletal elements, adapters, scaffolds). Raft clustering occurs at the plasma membrane as well as intracellularly, e.g., in endosomal lumen. Ligand binding or oligomerization can alter the partitioning of proteins in and out of rafts. Increased raft affinity of a given protein and its activation within rafts (e.g., phosphorylation by Src-family kinases [yellow]) can initiate a cascade of events, leading to further increase of raft size by clustering.