Interaction of membrane/lipid rafts with the cytoskeleton: Impact on signaling and function

Abstract

Summary The plasma membrane in eukaryotic cells contains microdomains that are enriched in certain glycosphingolipids, gangliosides, and sterols (such as cholesterol) to form membrane/lipid rafts (MLR). These regions exist as caveolae, morphologically observable flask-like invaginations, or as a less easily detectable planar form. MLR are scaffolds for many molecular entities, including signaling receptors and ion channels that communicate extracellular stimuli to the intracellular milieu. Much evidence indicates that this organization and/or the clustering of MLR into more active signaling platforms depends upon interactions with and dynamic rearrangement of the cytoskeleton. Several cytoskeletal components and binding partners, as well as enzymes that regulate the cytoskeleton, localize to MLR and help regulate lateral diffusion of membrane proteins and lipids in response to extracellular events (e.g., receptor activation, shear stress, electrical conductance, and nutrient demand). MLR regulate cellular polarity, adherence to the extracellular matrix, signaling events (including ones that affect growth and migration), and are sites of cellular entry of certain pathogens, toxins and nanoparticles. The dynamic interaction between MLR and the underlying cytoskeleton thus regulates many facets of the function of eukaryotic cells and their adaptation to changing environments. Here, we review general features of MLR and caveolae and their role in several aspects of cellular function, including polarity of endothelial and epithelial cells, cell migration, mechanotransduction, lymphocyte activation, neuronal growth and signaling, and a variety of disease settings.

The Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Active Subunit CdtB Contains a Cholesterol Recognition Sequence Required for Toxin Binding and Subunit Internalization

“…Furthermore, our observations demonstrate that Cdt-host cell association involves membrane microdomains enriched in cholesterol and is dependent upon the integrity of these so-called lipid rafts. Lipid rafts represent liquid-ordered microdomains which are distributed in the plasma membrane and whose lipid composition and high cholesterol content differ from the those of the rest of the membrane (52). Generally, lipid rafts are regarded as scaffolds for a number of molecular entities, which include ion channels, receptors, and signaling platforms; thus, these membrane regions provide an ideal structure to facilitate communication of extracellular stimuli to the intracellular milieu, leading to signaling events that regulate cell growth, proliferation, and survival (53,54).…”

Inhibition of CaV2.3 channels by NK1 receptors is sensitive to membrane cholesterol but insensitive to caveolin-1

“…The fourth probable explanation for the observed decrease of C m value due to MBCD treatment is the simplest one: cholesterol depletion changes the mechanoelastic properties of the plasma membrane [55, cf. 18] and its interaction with cytoskeletal components [16] which promote large changes in the geometry of the whole-cell configuration during the course of patch-clamp experiments. Even though this latter explanation is an attractive possibility, at the present time we have no direct evidence to support this hypothesis.…”

Gangliosphingolipids: Structure and Biological Roles

“…A variety of proteins have been shown to be raft-associated, such as GSL-anchored proteins in the extracellular leaflet [19], heterotrimeric G-proteins and src-family kinases related to signal transduction in the cytoplasmic leaflet, cytoskeletal components [20], receptor tyrosine kinases (RTKs), tetraspanins [21], but also adhesion molecules, such as integrins [22]. Lipid rafts are therefore highly dynamic structures containing specific lipids and proteins and can be seen as critical signalling platforms for many cellular functions, such as cell adhesion, growth, and migration (reviewed in [23]). GSLs, and especially gangliosides present in lipid rafts, can interact laterally with other molecules in their own membrane or with molecules present on other cells, and are therefore key molecules driving or modulating recognition and signalling events [24].…”