Membrane Rafts Caveolae in Signal Transduction

Membrane rafts and caveolae regulate a wide variety of cellular activities, including nutrient transport, endocytosis, exocytosis, transcytosis, viral entry and budding, as well as receptor and ion channel expression, activation and desensitization (Cohen et al. 2004; Liu et al. 2002; Morris et al. 2004; Parton and Simons 2007; van Deurs et al. 2003). The term "caveosome" has been proposed to identify a caveolin-containing endosome that mediates endocytosis in a manner akin to, but independent of, the clath-rin-coated pit/clathrin-coated vesicle endocytic pathway (Carver and Schnitzer 2003; Nichols 2003). Certain proteins, e.g., glycosylphosphatidylinositol (GPI)-linked proteins, preferentially localize in membrane rafts/caveolae. Important receptor-regulated events, e.g., shear-stress and calcium release, are among the cellular responses that occur in caveolae. Moreover, changes in expression or activity of rafts/caveolae have been implicated in aging and disease-associated alterations in cell function, including in signal transduction (Gratton et al. 2004; Park et al. 2004; Patel et al. 2007a,b; Ratajczak et al. 2003; Schutzer et al. 2005; Simons and Ehehalt 2002; van Deurs et al. 2003).

The raft/caveolar localization of signaling components, including GPCR pathway components, provides an arrangement whereby agonists can promote rapid, high fidelity activation of signaling pathways, especially pathways that require interaction of multiple proteins. The "caveolin signaling hypothesis" proposes that interaction of signaling proteins with the CSD (Fig. 1) regulates signal transduction events by sequestering components away from their signal transduction partners, such that in the "basal" state signaling is inhibited, but co-localization in caveolae facilitates the interaction of components upon activation of the signaling pathway (Cohen et al. 2004; Liu et al. 2002; Okamoto et al. 1998; van Deurs et al. 2003).

Fig. 1 (a) Electron micrograph showing caveolae on pulmonary artery smooth muscle cells. (b) Schematic depicting caveolae, caveolae resident proteins and proteins interacting with the caveolin scaffolding domain (CSD). G-protein coupled receptor (GPCR); adenylyl cyclase (AC); protein kinase A (PKA); protein kinase C (PKC); receptor tyrosine kinase (RTK); epidermal growth factor receptor (EGF-R); insulin receptor (I-R); platelet-derived growth factor receptor (PDGF-R); vascular endothelial growth factor receptor (VEGF-R); endothelial nitric oxide synthase (eNOS); mitogen activated protein kinase (MAPK)

Fig. 1 (a) Electron micrograph showing caveolae on pulmonary artery smooth muscle cells. (b) Schematic depicting caveolae, caveolae resident proteins and proteins interacting with the caveolin scaffolding domain (CSD). G-protein coupled receptor (GPCR); adenylyl cyclase (AC); protein kinase A (PKA); protein kinase C (PKC); receptor tyrosine kinase (RTK); epidermal growth factor receptor (EGF-R); insulin receptor (I-R); platelet-derived growth factor receptor (PDGF-R); vascular endothelial growth factor receptor (VEGF-R); endothelial nitric oxide synthase (eNOS); mitogen activated protein kinase (MAPK)

The co-expression of plasma membrane-localized GPCR, heterotrimeric (and certain low molecular weight) G-proteins and G-protein-regulated effectors in caveolae likely contributes to efficient activation and amplification of GPCR signaling events. In the following sections, we discuss classes of signal transduction proteins that localize in rafts/caveolae.

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