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Mini-Review |
Lattices, rafts, and scaffolds: domain regulation of receptor signaling at the plasma membrane
Correspondence to Ivan R. Nabi: ivan.robert.nabi{at}ubc.ca
The plasma membrane is organized into various subdomains of clustered macromolecules. Such domains include adhesive structures (cellular synapses, substrate adhesions, and cell–cell junctions) and membrane invaginations (clathrin-coated pits and caveolae), as well as less well-defined domains such as lipid rafts and lectin-glycoprotein lattices. Domains are organized by specialized scaffold proteins including the intramembranous caveolins, which stabilize lipid raft domains, and the galectins, a family of animal lectins that cross-link glycoproteins forming molecular lattices. We review evidence that these heterogeneous microdomains interact to regulate substratum adhesion and cytokine receptor dynamics at the cell surface.
P. Lajoie's present address is the Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY 10461.
J.G. Goetz's present address is Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid E-28029, Spain.
Abbreviations used in this paper: EGFR, epidermal growth factor receptor; GPI, glycosylphosphatidylinositol; STALL, stimulation-induced temporary arrest of lateral diffusion; TCR, T cell receptor.
© 2009 Lajoie et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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Introduction |
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 TopAbstract Introduction References |
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Lattices
Galectins are a family of lectins that bind Gal-GlcNAc branches of N-glycans of glycoproteins. Interaction of dimeric and pentameric galectins (Fig. 1) with multivalent cell surface glycoproteins promotes lattice formation (Demetriou et al., 2001; Ahmad et al., 2004; Partridge et al., 2004). Branched N-glycans, particularly tetraantennary structures generated by Golgi β1, 6N-acetylglucosaminyltransferase V (GlcNAc-TV; encoded by the Mgat5 gene), represent higher affinity ligands for galectins (Hirabayashi et al., 2002). The number of N-glycans present on glycoproteins also controls galectin affinity for glycosylated receptors (Lau et al., 2007). When added to the surface of neutrophils and endothelial cells, fluorescently conjugated galectin-3 (Gal-3) forms stable oligomers (Nieminen et al., 2007). Gal-3 binding also regulates diffusion rates of cell surface glycoprotein receptors and integrins (Lajoie et al., 2007; Goetz et al., 2008a). Lattices are therefore domains that function to promote homotypic and heterotypic interactions. However, the dynamics and composition of galectin lattices in different cell types remain to be determined.
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2-6 sialylation of N-glycans on integrins and the TRPV5 Ca2+ channel reduces binding to galectins (Cha et al., 2008; Zhuo et al., 2008), and may represent a general regulator of lattice avidity.
Rafts
Lipid rafts are dynamic cholesterol- and sphingolipid-rich membrane domains. Fluorescence resonance energy transfer, single particle tracking, and electron microscopy studies all support the concept of rafts as dynamic and transient nanoscale structures (Hancock, 2006). Lipid rafts may however fuse in response to signaling events into larger, more stable signal transduction platforms (Simons and Toomre, 2000).
Advances in temporal and spatial resolution using single particle tracking and stimulated emission depletion (STED) microscopy have highlighted the cholesterol-sensitive, subsecond (10–20 ms in <20-nm domains by STED) transient anchoring of raft-associated sphingolipids and glycosylphosphatidylinositol (GPI)-anchored proteins (Chen et al., 2006; Eggeling et al., 2009). The GPI-anchored CD59 receptor interacts frequently with its effector, Lyn kinase; but only after recruitment of G
2 does the CD59–Lyn complex stabilize, forming a domain (
50 nm in diameter) termed "stimulation-induced temporary arrest of lateral diffusion" (STALL). STALL is actin-dependent and cholesterol-sensitive, and replacing the GPI anchor of Lyn with a nonraft transmembrane domain limits STALL, implicating rafts in STALL formation (Fig. 1 A; Suzuki et al., 2007a,b). Cortical actin is also a critical determinant of the formation of cholesterol-sensitive GPI-anchored protein nanoclusters (Goswami et al., 2008). Transient recruitment and stabilization of signaling complexes within rafts thereby generates quantal signals whose integration produces the bulk cellular signaling response.
Scaffolds and noncaveolar Cav1
Oligomerized Cav1 microdomains, for which we propose the name "Cav1 scaffold," represent stable raft structures that may exhibit many of the signaling regulatory properties associated with Cav1. Cav1 is the major protein constituent of caveolae, smooth cholesterol-sensitive invaginations of the plasma membrane (Parton and Simons, 2007) whose formation also requires a cytoplasmic protein, PTRF-Cavin (Hill et al., 2008; Liu and Pilch, 2008). Caveolae are predicted to contain between 100 and 200 Cav1 molecules, but the minimal SDS-stable Cav1 oligomer contains only 15 Cav1 molecules (Monier et al., 1995; Parton et al., 2006) that may correspond to the Cav1 scaffold domain (Fig. 1). Indeed, even when expressed at low levels independently of caveolae formation, Cav1 still forms oligomers that are effectively immobile in the plasma membrane (Lajoie et al., 2007). As discussed below, noncaveolar functions of the Cav1 scaffold may include regulation of growth factor receptor signaling, raft-dependent endocytosis, and focal adhesion dynamics.
Cav1 is a well-characterized inhibitor of growth factor receptor signaling (Goetz et al., 2008b). For example, Cav1 interacts with EGF receptor (EGFR) via its 20–amino acid scaffolding domain and negatively regulates EGF responsiveness and EGFR lateral diffusion, even under conditions of reduced caveolae formation (Couet et al., 1997; Lajoie et al., 2007). Furthermore, EGFR distribution to morphologically defined caveolae by electron microscopy is evident only in cells treated with high levels of EGF (Sigismund et al., 2005). This suggests that in the absence of ligand, EGFR binds Cav1 outside of caveolae. Similarly, endothelial cell-specific expression of Cav1 reduces endothelial NOS activation but not plasma membrane caveolae, which suggests a functional role for noncaveolar Cav1 (Bauer et al., 2005).
Cav1 may function indirectly to regulate raft-dependent endocytosis by altering the lipid composition of raft domains (Lajoie and Nabi, 2007). Cav1 inhibition of the raft-dependent endocytosis of cholera toxin b subunit (CT-b) and dysferlin occurs independently of direct interaction with Cav1 or caveolae (Hernandez-Deviez et al., 2008; Lajoie et al., 2009). Overexpression of glycosphingolipids and cholesterol overrides negative regulation of raft-dependent endocytosis by Cav1 (Sharma et al., 2004). Cav1 binding to cholesterol and recruitment of cholesterol to raft domains (Murata et al., 1995; Smart et al., 1996) could induce both local and global changes in membrane lipid composition that impact on the dynamics, functionality, and endocytic potential of lipid rafts.
Cav1 is a substrate of Src kinase, and its tyrosine 14 phosphorylation (pY14Cav1) regulates its interaction with integrins, various signaling adapters, and protein tyrosine phosphatases (Goetz et al., 2008b). The ability of pY14Cav1 to induce ordered microdomains within focal adhesions as well as stabilize focal adhesion–associated FAK implicates pY14Cav1-mediated domain organization in the promotion of focal adhesion signaling and turnover leading to increased tumor cell migration (Gaus et al., 2006; Goetz et al., 2008a; Joshi et al, 2008). Structural differences between oligomerized Cav1 and pY14Cav1 scaffold domains remain unclear; however, both appear to regulate the formation of ordered lipid domains (Gaus et al., 2006; Parton and Simons, 2007). Collectively, stable Cav1 oligomers distinct from caveolae therefore form scaffolds that interact with proteins and lipids to regulate plasma membrane organization, cell surface signaling, and raft-dependent endocytosis (Fig. 1 B).
Domain interplay at the cell surface
Exchange of receptors between membrane domains is a critical aspect of cellular sensitivity to extracellular cues. Reduced T cell activation and autoimmunity in mice lacking Mgat5 and the galectin lattice is due to enhanced T cell receptor (TCR) clustering (Demetriou et al., 2001). In resting T cells, the Mgat5/galectin lattice partitions CD45 inside the raft immune synapse and partitions TCR–CD4-Lck–Zap-70 complexes outside the raft immune synapse, opposing cytoplasmic interactions with the actin cytoskeleton and TCR activation (Chen et al., 2007). Recruitment to the galectin lattice, promoted by metabolite flux through the hexosamine pathway (Grigorian et al., 2007), dampens TCR signaling and autoimmunity by sequestering TCR outside the immune synapse.
For EGFR and other cytokine receptors (including TGFβR, PDGFR, and insulin-like growth factor receptor [IGFR]), receptor recruitment to the galectin lattice potentiates ligand-induced clustering and signaling (Partridge et al., 2004). In mammary tumor cells, the Mgat5/galectin lattice sequesters EGFR, protecting them from interacting with Cav1 scaffolds, hence promoting growth factor signaling potential and tumor growth (Lajoie et al., 2007). Multivalent association of EGFR with the galectin lattice under conditions of higher N-glycan branching (i.e., Mgat5 activity) appears to be dominant over stable interaction of the receptor with Cav1 scaffolds.
pY14Cav1 promotion of FAK stabilization in focal adhesions is dependent on expression of Mgat5 and Gal-3 (Goetz et al., 2008a). In light of the ability of pY14Cav1 to induce raft-like domains within focal adhesions (Gaus et al., 2006), this is a clear example of microdomain interaction where the extracellular galectin lattice works in concert with intracellular pY14Cav1 scaffold domains to regulate focal adhesion dynamics and cell motility. The ability of the lattice to relieve EGFR suppression, to override Cav1 tumor suppressor activity, and to function with pY14Cav1 to promote tumor cell migration provides an elegant example of how membrane domains interact to regulate complex cell behavior (Fig. 2). The galectin lattice and raft domains therefore compete to regulate receptor signaling, with the lattice functioning as both a suppressor (TCR) and enhancer (EGFR, others) of receptor availability to the ligand, but they also synergize to promote integrin-dependent focal adhesion dynamics.
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Acknowledgments |
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Submitted: 12 November 2008
Accepted: 31 March 2009
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