Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling

Abstract

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. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.

Keywords: AC; AD; AJ; AMPAR; APC; APP; Alzheimer's disease; Aβ; CAM; CBD; CRAC; CSD; CTX; Cav; Caveola; Caveolin; Cytoskeleton; EC; ECM; FAK; Flot; G-protein-coupled receptor; GD; GJ; GM; GPCR; GPI; ICAM/VCAM; Ion channel; JAM; MLR; MT; Membrane/lipid raft; N-methyl-D-aspartate receptor; NMDAR; PTRF; PrP; RTK; Signaling receptor; T cell receptor; TCR; TEM; TJ; TRPC1; TSPN; Trk; VGCC; adenylyl cyclases; adherent junctions; alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor; amyloid beta peptide; amyloid precursor protein; antigen presenting cell; cAMP; cSMAC; caveolin; caveolin binding domain; caveolin scaffolding domain; cellular adhesion molecules; central supramolecular activation cluster; cholera toxin; cholesterol recognition/interaction amino acid consensus; cyclic adenosine 3′,5′ monophosphate; eNOS; endothelial cell; endothelial nitric oxide synthase (NOS3); extracellular matrix; flotillin; focal adhesion kinase; ganglioside disialic acid; ganglioside monosialic acid; gap junctions; glycosylphosphatidylinositol; inter/vascular CAM; junctional adhesion molecules; mGluR; membrane/lipid rafts; metabotropic glutamate receptor; microtubules; pMHC; peripheral major histocompatibility complex; polymerase I and transcript release factor; prion protein; receptor tyrosine kinases; tetraspanin; tetraspanin-enriched microdomains; tight junctions; transient receptor potential cation channel; tropomyosin receptor kinase; voltage-gated Ca(2+) channels.

Figure 1. Schematic depicting proposed caveolin monomer structures and oligomer complexes

A, Adapted from Fernandez et al. (2002), a model in which the caveolin-1 (Cav-1) scaffolding domain (CSD) is shown as an α-helix (AA 79–96) with Cav-1 oligomers composed of 7 monomers and an approximate diameter of 11 nm. This proposed heptamer forms because α-helical lateral interactions proximal to the cytofacial lipid bilayer give rise to a filamentous assembly 50 nm long. B, An alternative model by Hoop et al. (2012) in which the CSD is a β-strand (red/orange) separated by the wedged shaped α-helix (green barrels) within the cytofacial bilayer by cholesterol (yellow) interacting with a cholesterol recognition/interaction amino acid consensus (CRAC) motif (blue) with palmitoyl acids (brown strands) anchored to cysteine residues. C, Model by Whiteley et al. (2012) in which Cav-3 is arranged with 9 monomers assembled in a toroidal shape ~16.5 nm in diameter and 5.5 nm in height.

Figure 2. Membrane/lipid rafts and the endothelium barrier

Schematic depicting different types of MLR and how they serve to regulate endothelial cell (EC) morphology, adherence, and function. Scaffolding rafts secure the ECs to their surrounding environment [i.e., EC-EC adherence, EC-BL (basal lamina)adherence, and EC-lymphocyte adherence]. Integrins and cellular adhesion molecules(CAM) work in concert to bind to the extracellular matrix (ECM) and establish the adhesion raft with underlying BL. Occludins, claudins, zona occludins 1(ZO-1), and junctional adhesion molecules (JAMs) form the scaffolding raft of the interendothelial environemnt. Tetraspanins, caveolins/caveolae, and ICAM/VCAM (inter/vascular CAMs) form a lymphocyte adhesion raft (LAR), which facilitates lymphocyte recruitment and migration across the endothelium.

Figure 3. Membrane/lipid rafts and the epithelium barrier

Schematic illustrating the role of membrane/lipid rafts (MLR) in epithelial apical-basal polarity. MLR form unique plasmalemma outward (cilium and microvilli) and invaginations (deep tubules). MLR and associated scaffolds also establish tight junctions (TJ), adherent junctions (AJ), gap junctions (GJ), tetraspaninenriched microdomains (TEM), caveolin-enriched microdomains/caveolar membranes. Scaffolding and cholesterol-binding proteins such as caveolin and prominin as well as junctional adhesion molecules (JAM), zona occludins (ZO), cadherins, and connexins all participate as signaling platforms, sites for intercellular adherence and for actin cytoskeletal tethering in order to create a barrier from the outside environment but also regions that deliver molecules, nutrients, and ions into cells and ultimately to host organisms.

Figure 4. Membrane/lipid rafts, growth cone advancement and axonal guidance

Series of schematics depicting MLR (red PM) at the leading edge of a neuronal growth cone. This polarity and forward migration of the axonal growth cone cannot occur without MLR and the underlying actin (blue) and tubulin (green) cytoskeleton. Inset A shows a closer illustration of the growth cone with MLR at the leading tips receiving extracellular guidance cues and also tethering and transducing those cues to the filamentous (F-) actin. The axonal microtubule (MT)-associated protein Tau cross-links adjacent MT to maintain axonal integrity and facilitate guidance. Inset B shows a close up of several important MLR signaling receptors and enzymes (AMPAR, Trk, SFK, Rho GTPases), scaffolds (caveolin, flotillin, tetraspanin), and adhesion molecules (integrins, NCAM or neuronal cellular adhesion molecule). F-actin binding proteins such as filamin anchor F-actin to MLR scaffold proteins.

Figure 5. Membrane/lipid rafts and the immunologic synapse

Panel A, or pre-activation state, depicts an antigen presenting cell (APC) that is presenting peptide antigens extracellularly via the major histocompatibility complex (pMHC) to the T cell receptor (TCR) located within MLR located in the central supramolecular activation cluster (cSMAC). APC and T cells connect via cell adhesion molecules (integrins) located within tetraspanin-enriched microdomains (TEMs) located in the peripheral supramolecular activation cluster (pSMAC). Panel B, or activation state, shows that after TCR-pMHC interactions, the pSMAC MLR migrates laterally towards the cSMAC via actin cytoskeletal rearrangement. cSMAC regulates termination of the signaling through subsequent TCR downregulation.