Membrane/cytoskeleton communication.

Accumulations of particular lipids in ordered arrays in the membrane (termed microdomains or lipid rafts) can attract proteins with specific targeting domains. Both the lipid and protein components of rafts communicate with the cytoskeleton directly thereby regulating cellular responses. Recent evidence implicating phosphoinositide 1,5 bisphosphate (PIP2) in cytoskeletal regulation shows that agonist sensitive regulation of PIP2 homoeostasis occurs specifically rafts, which appear to provide a major structural substrate for its function. The crucial role of PIP2 in generating cytoskeletal responses is chiefly achieved by regulating proteins that control actin dynamics directly. Many of these regulatory proteins are also specifically enriched in rafts either directly (by insertion into the lipid bilayer via acetylation motifs), or indirectly via interactions with other raft components. The notion that rafts form membrane platforms or modules that mediate signaling responses has been most extensively demonstrated in the immune synapse (IS) of T cells, a complex assemblage of rafts that integrates signaling cascades originating from the simultaneous activation of a wide variety of receptors. The IS is essential for both the amplification and maintenance of T-cell activation, and its assembly at the antigen presenting site depends on the interactions between rafts and the actin cytoskeleton that regulates coalescence of smaller raft components into the larger IS complex. Likewise the neuron, which represents the most highly polarized cell in the body, utilizes the regulation of actin dynamics in response to a plethora of extracellular signals to control axon pathfinding thereby sculpting nervous system cytoarchitecture with utmost precision. It is now becoming clear, that as in the T-cell, lipid rafts in the growing axon can assemble into highly specific, yet malleable and dynamic, signaling modules that regulate actin dynamics in a fashion that is also PIP2-dependent and that utilizes both familiar and novel regulatory mechanisms. It seems clear that raft mediated cytoskeletal regulation represents a highly conserved mechanism to integrate cellular responses to diverse signals.