Multivalent Scaffold Proteins and Membrane Rafts:- Membrane Rafts and Caveolae May Segregate Signaling Proteins
Membrane rafts are regions of the membrane bilayer enriched in sphingolipids, sterols, and certain proteins; in cluding many attached to the bilayer by GPI anchors. Some receptor Tyr kinases, such as the receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), appear to be localized in rafts; other signaling proteins, such as the small G protein Ras (which is prenylated) and the hetero trimeric G protein Gs (also prenylated, on the α and γ subunits), are not. Growing evidence suggests that this sequestration of signaling proteins is functionally significant. When cholesterol is removed from rafts by treat ment with cyclodextrin (which binds cholesterol and removes it from membranes), the rafts are disrupted and a number of signaling pathways become defective. How might localization in rafts influence signaling through a receptor? There are several possibilities. If a receptor Tyr kinase in a raft is phosphorylated, and the phosphotyrosine phosphatase that reverses this phosphorylation is in another raft, then dephosphorylation of the Tyr kinase will be slowed or prevented. If two signaling proteins must interact during transduction of a signal, the probability of encounters between these proteins is greatly enhanced if both are in the same raft. Interactions between scaffold proteins might be strong enough to pull into a raft a signaling protein not normally located there, or strong enough to pull receptors out of a raft. For example, the EGF receptor in isolated fibroblasts is normally concentrated in the specialized rafts called caveolae , but treatment with EGF causes the receptor to leave the raft. This migration depends on the receptor’s protein kinase activity; mutant receptors lacking this activity remain in the rafts during treatment with EGF. Caveolin, an integral membrane protein localized in caveolae, is phosphorylated on Tyr residues in response to insulin, and phosphorylation may allow the now-activated EGF receptor to draw its binding partners into the raft. Finally, another example of the clustering of signaling proteins in rafts is the -adrenergic receptor. This receptor is segregated in membrane rafts that also contain the G proteins, adenylyl cyclase, PKA, and a specific protein phosphatase, PP2, providing a highly integrated signaling unit. Spatial segregation of signaling proteins in rafts adds yet another dimension to the already complex processes initiated by extracellular signals.
