A Close Association of the Ganglioside-specific Sialidase Neu3 with Caveolin in Membrane Microdomains

Wang, Yan; Yamaguchi, Kazunori; Wada, Tadashi; Hata, Keiko; Zhao, Xin; Fujimoto, Toyoshi; Miyagi, Taeko

doi:10.1074/jbc.m110515200

Cited by 115 publications

(97 citation statements)

References 32 publications

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“…In addition to the glycolipid products, NEU3 might exert an influence on the signaling by interacting with some related molecules including EGFR, as shown in Figure 5c. It is feasible because we found previously that NEU3 actually interacts with caveolin-1 (Wang et al, 2002) or Grb-2 (Sasaki et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells

et al. 2007

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Section: Discussionmentioning

confidence: 99%

A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells

et al. 2007

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“…Furthermore, recent results show that the enzyme is localized in the Triton X-100-resistant microdomains (i.e. 'classical' GEM) where it interacts with caveolin [40,41]. Then how can one explain the effect of Neu3 on the interactions of the protein, which is excluded from the classical lipid rafts?…”

Section: Discussionmentioning

confidence: 99%

Gangliosides play an important role in the organization of CD82-enriched microdomains

Odintsova

Butters

Monti

et al. 2006

Biochemical Journal

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Four-transmembrane-domain proteins of the tetraspanin superfamily are the organizers of specific microdomains at the membrane [TERMs (tetraspanin-enriched microdomains)] that incorporate various transmembrane receptors and modulate their activities. The structural aspects of the organization of TERM are poorly understood. In the present study, we investigated the role of gangliosides in the assembly and stability of TERM. We demonstrated that inhibition of the glycosphingolipid biosynthetic pathway with specific inhibitors of glucosylceramide synthase [NB-DGJ (N-butyldeoxygalactonojirimycin) and PPMP (D-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol · HCl)] resulted in specific weakening of the interactions involving tetraspanin CD82. Furthermore, ectopic expression of the plasmamembrane-bound sialidase Neu3 in mammary epithelial cells also affected stability of the complexes containing CD82: its association with tetraspanin CD151 was decreased, but the association with EGFR [EGF (epidermal growth factor) receptor] was enhanced. The destabilization of the CD82-containing complexes upon ganglioside depletion correlated with the re-distribution of the proteins within plasma membrane. Importantly, depletion of gangliosides affected EGF-induced signalling only in the presence of CD82. Taken together, our results provide strong evidence that gangliosides play an important role in supporting the integrity of CD82-enriched microdomains. Furthermore, these results demonstrate that the association between different tetraspanins in TERM is controlled by distinct mechanisms and identify Neu3 as a first physiological regulator of the integrity of these microdomains.

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“…Alternatively, an indirect interaction of GM3 with caveolin-1 via an adaptor molecule with an extracellular domain is another possibility. The mechanism by which GM3 content affects caveolin-1 transport may also be explained by the recent recognition that the plasma membrane ganglioside-specific sialidase is enriched in caveolar domains in close association with caveolin-1 and binds directly to the caveolin-1 in HeLa cells and COS-1 cells (48). Given that GM3 is a substrate for this plasma membrane ganglioside-specific sialidase, the binding of GM3 to this membrane sialidase may compete with caveolin-1 for binding to the sialidase, thus releasing or promoting continued attachment with the caveolin-1 depending on GM3 content.…”

Section: Discussionmentioning

confidence: 99%

Ganglioside Induces Caveolin-1 Redistribution and Interaction with the Epidermal Growth Factor Receptor

Wang

Sun

Paller

2002

Journal of Biological Chemistry

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Although caveolin-1 is thought to facilitate the interaction of receptors and signaling components, its role in epidermal growth factor receptor (EGFR) signaling remains poorly understood. Ganglioside GM3 inhibits EGFR autophosphorylation and may thus affect the interaction of caveolin-1 and the EGFR. We report here that endogenous overexpression of GM3 leads to the clustering of GM3 on the cell membrane of the keratinocyte-derived SCC12 cell line and promotes co-immunoprecipitation of caveolin-1 and GM3 with the EGFR. Overexpression of GM3 does not affect EGFR distribution but shifts caveolin-1 to the detergent-soluble, EGFR-containing region; consistently, caveolin-1 is retained in the detergent-insoluble membrane when ganglioside is depleted. GM3 overexpression inhibits EGFR tyrosine phosphorylation and receptor dimerization and concurrently increases both the content and tyrosine phosphorylation of EGFR-associated caveolin-1, providing evidence that tyrosine phosphorylation of caveolin-1 inhibits EGFR signaling. Consistently, depletion of ganglioside both increases EGFR phosphorylation and prevents the EGF-induced tyrosine phosphorylation of caveolin-1. GM3 also induces delayed serine phosphorylation of EGFR-unassociated caveolin-1, suggesting a role for serine phosphorylation of caveolin-1 in regulating EGFR signaling. These studies suggest that GM3 modulates the caveolin-1/EGFR association and is critical for the EGF-induced tyrosine phosphorylation of caveolin-1 that is associated with its inhibition of EGFR activation.The plasma membrane of eukaryotic cells is not uniform and instead is composed of microdomains or rafts, highly dynamic lateral assemblies composed of glycosphingolipids and cholesterol. One form of these rafts, caveolae, has been distinguished ultrastructurally by its invaginated shape and by the presence of caveolin-1, the major structural protein of caveolae. These caveolin-containing rafts are insoluble in both nonionic detergents, such as Triton X-100, and in sodium carbonate at alkaline pH and can be isolated as low density fractions by sucrose density gradient. Although caveolae have been implicated as sites at which receptors and signaling molecules interact (1, 2), signaling also occurs at noninvaginated rafts, devoid of caveolin-1 but enriched in glycosphingolipids (3-5). In addition, caveolin-1 may also exist in lipid rafts without caveolae (6). The distinction between lipid rafts and caveolae and the attribution of specific biologic functions and signaling pathways to one or the other remains confusing in the literature (7).Caveolae have been proposed to be the site of epidermal growth factor receptor (EGFR) 1 signaling, including EGFR autophosphorylation, based largely on the demonstration that caveolin-1 and EGFR both co-localize to low density, carbonateinsoluble membrane regions (8 -11). However, caveolin-1 and EGFR can be separated by differences in solubility in nonionic detergent, with EGFR restricted to the detergent-soluble high buoyancy, low density membrane regions (1...

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A Close Association of the Ganglioside-specific Sialidase Neu3 with Caveolin in Membrane Microdomains

Cited by 115 publications

References 32 publications

A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells

A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells

Gangliosides play an important role in the organization of CD82-enriched microdomains

Ganglioside Induces Caveolin-1 Redistribution and Interaction with the Epidermal Growth Factor Receptor

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