Regulation of raft-dependent endocytosis

Abstract

Raft-dependent endocytosis is in large part defined as the cholesterol-sensitive, clathrin-independent internalization of ligands and receptors from the plasma membrane. It encompasses the endocytosis of caveolae, smooth plasmalemmal vesicles that form a subdomain of cholesterol and sphingolipid-rich lipid rafts and that are enriched for caveolin-1. While sharing common mechanisms, like cholesterol sensitivity, raft endocytic routes show differential regulation by various cellular components including caveolin-1, dynamin-2 and regulators of the actin cytoskeleton. Dynamin-dependent raft pathways, mediated by caveolae and morphologically equivalent non-caveolin vesicular intermediates, are referred to as caveolae/raft-dependent endocytosis. In contrast, dynamin-independent raft pathways are mediated by non-caveolar intermediates. Raft-dependent endocytosis is regulated by tyrosine kinase inhibitors and, through the regulation of the internalization of various ligands, receptors and effectors, is also a determinant of cellular signaling. In this review, we characterize and discuss the regulation of raft-dependent endocytic pathways and the role of key regulators such as caveolin-1.

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Raft-dependent endocytosis and its regulation by Cav1. (A) Several endocytic pathways are characterized as raft-dependent and mediate the uptake of various ligands, including but not limited to those indicated. These include dynamin-dependent pathways that invoke caveolae or non-caveolin vesicular intermediates and that can be referred to as caveolae/raft-dependent endocytosis [14]. Dynamin-independent pathways invoke non-caveolar tubular intermediates. While similar mechanisms control the uptake of the indicated raft-dependent ligands, they are not necessarily internalized by the same raft domains or follow similar intracellular targeting routes. (B) Cav1 may negatively regulate uptake via the dynamin-dependent, non-caveolin pathway by either stabilizing raft invaginations at the cell surface (1) or by sequestering key components, including cholesterol, dynamin and others, required for raft-dependent uptake (2). Cholesterol is not shown in the flat portion of the membrane to simplify the diagram. LacCer:lactosylceramide; CT-b: cholera toxin b subunit; GPI-AP: glycosylphosphatidylinositol-anchored proteins; AMF: autocrine motility factor; IL-2: interleukin-2; SV40:simian virus 40.