Specialized membrane microdomains defined by submembranous protein networks

In addition to those which may be defined by TM protein- or glycocalix-based fences and others which may depend on particular lipid clusters (caveolae), other membrane microdomains may be defined by the subplasmalemmal assembly of various types of protein skeletons. These endoskeletal networks may recruit a selection of peripheral and cytosolic proteins, with the eventual connection of a membrane patch to the actin microfilaments. At least four types of microdomains may be defined, the first one being mostly an endoskeleton, the next two involving TM proteins with intercellular adhesion sites, and the last one concerning microvilli and possibly ligand recognition.

In erythrocytes, a spectrin-based filamentous network is apposed to the inner face of the lipid bilayer, conferring mechanical support to the membrane. Several members of the spectrin family occur as endoskeletal components of nonerythroid cells (ankyrin, fodrin, TW260/240, dystrophin, dystro-phin-related protein, a-actinin). These proteins constitute membrane skeletons with a fixed stoichi-ometry but a flexible morphology (due to the properties of spectrin). They help to organize and stabilize microdomains which are enriched in some integral membrane proteins. None of these skeletal proteins is a TM protein, i.e. they cannot be directly in touch with the cell outside, but one of them (often ankyrin) can link the assembly to a TM protein (often a channel or transporter). Moreover, most of these proteins bind to actin, providing specific attachment sites for cytoskeletal components; the latter may thus define the topographical distribution and cell surface dynamics of such microdomains whose occurrence in leukocytes remains unknown.

Integrin-mediated adhesion to the extracellular matrix reveals the colocalization of two submem-branous skeleton proteins, ot-actinin and talin; these actin-binding proteins connect the cytosolic domains of integrins to a matrix of actin microfilaments and other actin-binding proteins, including vinculin, pax-illin, tensin and zyxin. Cadherin-mediated adhesion similarly results in the localized recruitment to their cytosolic domain of several cytosolic proteins ((3-cat-enin, plakoglobin, pl20) which bind to a-catenin (homologous to vinculin), itself binding to fodrin and actin, with a-actinin joining the complex. In both the integrin and the cadherin cases, the networks of interacting submembranous skeletal proteins strengthen cell adhesion and provide protein scaffolds for signaling networks, which involve kinases, phosphatases, GTP-binding proteins and adaptor proteins.

Another actin-based cytoskeleton characterizes the noncontacting surface of epithelial cells, i.e. its apical surface which expresses numerous microvilli. Each microvillus is sustented by a bundle of actin filaments, cross-linked by villin and fimbrin, coupled laterally to the membrane by myosin I, and anchored into the cortical actin filament network by fodrin. In the case of epithelial/endothelial borders, the microvilli are found on the apical surfaces of the cells, thus facing the 'not self' in the lumen. Would adhesion through the integrin- and cadherin-based domains be rather involved in recognition of self, whereas microvillus-based recognition would be devoted to the not self? In the case of lymphoid cells, microvilli tend to redistribute to the area of contact with the target cell, possibly showing their direct involvement as an early recognition step. Assuming the analogy to epithelial cells goes further, lymphocyte microvilli might not mediate adhesion, but only be involved in signaling ligand recognition.

Another case for specialized membrane micro-domains is found on the apical surface of epithelial cells: these are the caveolae which are 50-100 nm invaginations found at the bases of the apical microvilli. These membrane protein-lipid micro-domains are remarkably resistant to detergent (e.g. Triton-X100)-mediated solubilization. They are coated with caveolin, a TM protein which is a v-Src substrate, and they contain G protein-coupled receptors; in caveolae, caveolin exists as a hetero-oligomeric complex with integral proteins and known cytosolic signaling molecules, suggesting the involvement of caveolae in transmembrane signaling. Moreover, caveolae would recruit and 'cluster' GPI proteins (in a 'promiscuity' sense), such as the folate-binding protein (showing their important physiological role). In T cells, GPI proteins (e.g. Thy-1 or DAF[CD55J) may play a role in signal transduction, particularly through an activation of sub-membranous protein tyrosine kinases (e.g. Fyn or Lck), which are proteins anchored to the inner leaflet of the lipid bilayer by N-terminal myristoylation. It is assumed that the connection (as found by coimmunoprecipitation) of the latter proteins to the extracellular GPI proteins (whose anchor is restricted to the outer leaflet of the lipid bilayer) might be done by the TM protein caveolin.

Finally, the topography of the various micro-domains might be determined on the cell surface by-anchorage of the various scaffolds to the microtubu-lar cytoskeleton. As suggested for the epithelial cell model, microtubule organization might confer a polarity to the lymphocyte for microdomain redistribution to the cap/uropod area.

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