Actin cytoskeleton regulation through modulation of PI(4,5)P2 rafts

The phosphoinositide lipid PI(4,5)P-2 is now established as a key cofactor in signaling to the actin cytoskeleton and in vesicle trafficking. PI(4,5)P-2 accumulates at membrane rafts and promotes local co-recruitment and activation of specific signaling components at the cell membrane. PI(4,5)P-2 rafts may thus be platforms for local regulation of morphogenetic activity at the cell membrane. Raft PI(4,5)P-2 Is regulated by lipid kinases (PI5-kinases) and lipid phosphatases (e.g. synaptojanin). In addition, GA-P43-like proteins have recently emerged as a group of PI(4,5)P-2 raft-modulating proteins. These locally abundant proteins accumulate at inner leaflet plasmalemmal rafts where they bind to and co-distribute with PI(4,5)P-2, and promote actin cytoskeleton accumulation and dynamics. In keeping with their proposed role as positive modulators of PI(4,5)P-2 raft function, GA-P43-like proteins confer competence for regulated morphogenetic activity on cells that express them. Their function has been investigated extensively in the nervous system, where their expression promotes neurite outgrowth, anatomical plasticity and nerve regeneration. Extrinsic signals and intrinsic factors may thus converge to modulate PI(4,5)P-2 rafts, upstream of regulated activity at the cell surface.