Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR

Odintsova, Elena; Voortman, Jens; Gilbert, Elizabeth R.; Berditchevski, Fedor

doi:10.1242/jcs.00793

Cited by 121 publications

(125 citation statements)

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“…16 Tetraspanins are also known to form a specific kind of membrane domains, 46 interact with GSL 18,47 and modulate EGFR signaling. 48 Therefore, TI-VAMPdependent regulation of EGFR may result from its role in transport of components of membrane domains.…”

Section: Discussionmentioning

confidence: 99%

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

et al. 2015

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Keywords: exocytosis, Golgi apparatus, SNARE, sphingolipids, TI-VAMP/VAMP7 Abbreviations: BFA, Brefeldin A; Cer, Ceramide; ER, Endoplasmic Reticulum; GlcCer, Glucosylceramide; GM3, ganglioside monosialic acid 3; GPI, Glycosylphosphatidylinositol; GSL, Glycosphingolipids; LC, Long Chain; PI, Phosphatidylinositide; PM, Plasma Membrane; SM, Sphingomyelin; TGN, D Trans-Golgi Network; TI-VAMP/VAMP7, Tetanus neurotoxin-insensitive vesicle-associated membrane protein / Vesicle associated membrane protein 7; VLC, very long vhain; VSVG, Vesicular Stomatitis Virus GlycoproteinBiological membranes in eukaryotes contain a large variety of proteins and lipids often distributed in domains in plasma membrane and endomembranes. Molecular mechanisms responsible for the transport and the organization of these membrane domains along the secretory pathway still remain elusive. Here we show that vesicular SNARE TI-VAMP/VAMP7 plays a major role in membrane domains composition and transport. We found that the transport of exogenous and endogenous GPI-anchored proteins was altered in fibroblasts isolated from VAMP7-knockout mice. Furthermore, disassembly and reformation of the Golgi apparatus induced by Brefeldin A treatment and washout were impaired in VAMP7-depleted cells, suggesting that loss of VAMP7 expression alters biochemical properties and dynamics of the Golgi apparatus. In addition, lipid profiles from these knockout cells indicated a defect in glycosphingolipids homeostasis. We conclude that VAMP7 is required for effective transport of GPI-anchored proteins to cell surface and that VAMP7-dependent transport contributes to both sphingolipids and Golgi homeostasis.

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Section: Discussionmentioning

confidence: 99%

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

et al. 2015

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“…19,20 To investigate whether c-Met-CD82 complex is a part of the large cluster of the CD82 protein complex, we performed immunoprecipitation experiments using the anti-c-Met and anti-CD82 antibodies.…”

Section: Cd82/kai-1 Associates With C-met On Carcinoma Cellsmentioning

confidence: 99%

Regulation of c‐Met signaling by the tetraspanin KAI‐1/CD82 affects cancer cell migration

Takahashi

Sugiura

Abé

et al. 2007

Intl Journal of Cancer

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It has been proposed that the metastasis suppressor CD82/KAI-1, which is a member of the tetraspanin superfamily, regulates biological activity by associating with cell surface receptors or proteins. We show a novel association between CD82 and the hepatocyte growth factor (HGF) receptor c-Met. Although ectopic expression of CD82 in nonsmall cell lung carcinoma cells did not affect the tyrosine phosphorylation of c-Met, these cells showed significant suppression of HGF-induced lamellipodial protrusion and cell migration. CD82 selectively attenuated c-Met signaling via the Ras-Cdc42/Rac and the phosphatidylinositol 3-kinase/ Cdc42/Rac pathways. In contrast, another c-Met signaling pathway that involves phosphatidylinositol 3-kinase/Akt and phosphatidylinositol 3-kinase/mitogen activated protein kinase was not affected by CD82. Signaling adapter proteins for c-Met, such as Grb2 and p85, exhibited reduced association with c-Met in cells that ectopically expressed CD82. These results indicate that the CD82-c-Met complex inhibits HGF-induced cancer cell migration by the inactivation of small GTP-binding proteins of the Rho family via c-Met adapter proteins. ' 2007 Wiley-Liss, Inc.Key words: CD82/KAI-1; HGF; c-Met; cell migration; signaling Invasion and metastasis are characteristic features of malignant tumors. Cancer cell invasion depends on a complex series of steps consisting of cell migration, cell adhesion and matrix degradation. Of these events, cancer cell migration is essential for invasion and metastasis.The c-Met protein, which is the receptor for hepatocyte growth factor (HGF), is crucial for the control of tumor cell invasive growth. 1,2 A direct role for c-Met in the metastatic behavior of human tumors has been proposed. 3,4 For example, in colorectal carcinoma, amplification of the Met gene provides a selective advantage that favors metastasis in the liver. 5 The carboxy-terminal domain of the c-Met receptor includes 2 critical tyrosine residues, Y1349 and Y1356, which upon phosphorylation form a multifunctional docking site for multiple transducers and adapters. The adapter proteins growth factor receptorbound protein 2 (Grb2) and GRB-associated binder 1 (Gab1) are essential for the initiation of signaling pathways for various downstream targets. 6,7 Among these downstream targets, the Ras-and phosphatidylinositol 3-kinase (PI3K)-dependent pathways are required to trigger cell proliferation, motility and survival. 8,9 Tetraspanins, or TM4SF proteins, compose a large group of cell surface transmembrane proteins, some of which can form complexes with integrins. Several tetraspanins appear to be particularly relevant to tumor cell metastasis. 10,11 CD82/KAI-1, which is a member of the tetraspanin superfamily, was originally identified as an accessory molecule in T-cell activation. 12 The role of CD82 in cancer progression was discovered during a genetic screen to identify metastasis suppressor genes. 13 Ample evidence exists to suggest that CD82/KAI1 acts as a broad-spectrum suppressor of invasion and me...

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“…Tetraspanins lack intrinsic activity and their effects are mediated by protein interactions. Several different proteins have been shown to associate with CD82 (Yunta and Lazo, 2003), including a3b1, a4b1, a5b1, and a6b1 integrins (Berditchevski and Odintsova, 1999;Berditchevski, 2001;Yunta and Lazo, 2003); the serine/threonine kinase PKCa (Berditchevski and Odintsova, 1999;Berditchevski, 2001;Zhang et al, 2001); B-cell receptors CD4, CD8, and CD19 (Imai et al, 1995;Mannion et al, 1996;Hammond et al, 1998); other tetraspanins including CD81, CD63, and CD9 (Vogt et al, 2002); receptor tyrosine kinases EGFR and ErbB2 (Odintsova et al, 2000(Odintsova et al, , 2003; an Ig super family molecule EW12 (Zhang et al, 2003b); and a newly identified tetraspanin molecule, kitenin, which is expressed in gastric cancers (Lee et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

2005

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KAI1/CD82, a tetraspanin protein, was first identified as a metastasis suppressor in prostate cancer. How loss of CD82 expression promotes cancer metastasis is unknown. Restoration of CD82 expression to physiological levels in the metastatic prostate cell line PC3 inhibits integrinmediated cell migration and invasion, but does not affect integrin expression. Integrin-dependent activation of the receptor kinase c-Met is dramatically reduced in CD82-expressing cells, as is c-Met activation by its ligand HGF/ SF. CD82 expression also reduced integrin-induced activation and phosphorylation of the cytoplasmic tyrosine kinase Src, and its downstream substrates p130Cas and FAK Y861. Inhibition of c-Met expression or Src kinase function reduced matrigel invasion of PC3 cells to the same extent as CD82 expression. These data indicate that CD82 functions to suppress integrin-induced invasion by regulating signaling to c-Met and Src kinases, and suggests that CD82 loss may promote metastasis by removing a negative regulator of c-Met and Src signaling.

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Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR

Cited by 121 publications

References 56 publications

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

Regulation of c‐Met signaling by the tetraspanin KAI‐1/CD82 affects cancer cell migration

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

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