Compartmentalization of the Exocyst Complex in Lipid Rafts Controls Glut4 Vesicle Tethering

Inoue, Mayumi; Chiang, Shian-Huey; Chang, Louise; Chen, Xiao Wei; Saltiel, Alan R.

doi:10.1091/mbc.e06-01-0030

Cited by 108 publications

(142 citation statements)

References 52 publications

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“…Our question arising here is whether RalA acts upstream or downstream of Rheb in the nutrient-sensing system, because RalA may exert its effect on diverse processes, such as cytoskeletal reorganization and membrane dynamics (19 -22), which potentially influence the nutrient uptake process. In fact, a Ral effector, the exocyst complex, is involved in vesicle transport (20,39,40); Exo70, an exocyst component, plays a role in targeting of the glucose transporter 4 to the plasma membrane (41,42). Therefore, we first FIGURE 2.…”

Section: Resultsmentioning

confidence: 99%

RalA Functions as an Indispensable Signal Mediator for the Nutrient-sensing System

Maehama

Tanaka

Nishina

et al. 2008

Journal of Biological Chemistry

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Cells sense nutrients present in the extracellular environment and modulate the activities of intracellular signaling systems in response to nutrient availability. This study demonstrates that RalA and its activator RalGDS participate in nutrient sensing and are indispensable for activation of mammalian target of rapamycin complex 1 (mTORC1) induced by extracellular nutrients. Knockdown of RalA or RalGDS abolished amino acidand glucose-induced mTORC1 activation, as judged by phosphorylation of S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1. The amount of GTP-bound RalA increased in response to increased amino acid availability. In addition, RalA knockdown suppressed Rheb-induced S6 kinase phosphorylation, and the constitutively active form of RalA induced mTORC1 activation in the absence of Rheb. These results collectively suggest that RalGDS and RalA act downstream of Rheb and that RalA activation is a crucial step in nutrient-induced mTORC1 activation.Nutrients such as amino acids and carbohydrates are available in the extracellular space and are vital for cell homeostasis. Cells are able to detect extracellular nutrients and modulate their intracellular signaling systems in response to changes in nutrient levels. Recent studies have shown that mammalian target of rapamycin complex 1 (mTORC1) 2 functions as a critical intracellular component of the nutrient-sensing system and governs many aspects of cellular responses to changing nutrient levels (1-5). Signaling cascades initiated by growth factors and leading to mTORC1 activation have been extensively characterized. Growth factor stimulation results primarily in the phosphorylation of TSC2, a GTPase-activating protein (GAP) for Rheb GTPase, in a phosphoinositide 3-kinase-and protein kinase B (PKB)-dependent manner, followed by inactivation of TSC2 GAP activity (6 -9). It has been proposed that the decreased GAP activity allows Rheb to stay in an "active" GTPbound form, leading to mTORC1 activation. In contrast to the mechanism of the growth factor-initiated mTORC1 activation, little is known about the mechanism(s) by which mTORC1 activity is regulated by amino acid availability (10 -16). Recent studies have shown that calmodulin and hVps34 play a role in the amino acid-sensing system (12) and that Rag GTPases escort mTORC1 to sites where they can activate the kinase (17, 18). However, most of the amino acid-sensing signaling machinery, including the amino acid sensors themselves, is unknown, and the mechanism(s) underlying the nutrient-sensing process remains to be identified.RalA and RalB GTPases belong to the Ras superfamily and are known to participate in multiple cellular processes through binding to diverse effector proteins. RalA effectors described to date include Ral-binding protein 1, Sec5, Exo84, filamin, and ZO-1-associated nucleic acid-binding protein (19 -22); these interactions are indicative of crucial roles for RalA in cell migration, membrane dynamics, and transcriptional regulation. RalB is highly homologous to R...

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Section: Resultsmentioning

confidence: 99%

RalA Functions as an Indispensable Signal Mediator for the Nutrient-sensing System

Maehama

Tanaka

Nishina

et al. 2008

Journal of Biological Chemistry

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“…19,40 GLUT1 and GLUT4 are known to function in membrane domains. 41,42 In addition, phospholipase D1 (PLD1) is transported in VAMP7 vesicles, controls its fusion capacity 43 and is an effector of Arf1 44,45 so that the absence of VAMP7 could alter Golgi lipidic content and confer BFA-resistance via an accumulation or altered activity of PLD1 at the TGN. The activity of other enzymes involved in lipid metabolism particularly those regulating GSL biosynthesis at the Golgi might be also altered as a result of the absence of VAMP7 (see below).…”

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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“…The docking of GLUT4 vesicles with the plasma membrane appears to require the Exocyst complex that is formed from the assembly of 8 distinct proteins [29][30][31][32]. In the case of GLUT4, the Exo70, Sec6 and Sec8 protein component of this complex redistribute to the plasma membrane in response to insulin [29] These events are triggered by the insulin activation of a small GTP binding protein TC10 that recruits Exo70 with Sec6 and Sec8 to lipid raft microdomains in the plasma membrane [33,34]. Moreover, Sec8 associates with the PDZ domain of SAP97 a MAGUK (membrane-associated guanylate kinase) family member that is recruited along with Sec8 [33].…”

Section: Glut4 Vesicle Docking and Plasma Membrane Fusionmentioning

confidence: 99%

“…In the case of GLUT4, the Exo70, Sec6 and Sec8 protein component of this complex redistribute to the plasma membrane in response to insulin [29] These events are triggered by the insulin activation of a small GTP binding protein TC10 that recruits Exo70 with Sec6 and Sec8 to lipid raft microdomains in the plasma membrane [33,34]. Moreover, Sec8 associates with the PDZ domain of SAP97 a MAGUK (membrane-associated guanylate kinase) family member that is recruited along with Sec8 [33]. Interestingly, expression of a dominant-interfering Exo70 protein or siRNA-mediated knockdowns did not prevent GLUT4 vesicle trafficking to the plasma membrane but did inhibit GLUT4 plasma membrane fusion whereas over expression of Sec6 and Sec8 enhanced GLUT4 translocation to the plasma membrane [33,35].…”

Section: Glut4 Vesicle Docking and Plasma Membrane Fusionmentioning

confidence: 99%

“…Moreover, Sec8 associates with the PDZ domain of SAP97 a MAGUK (membrane-associated guanylate kinase) family member that is recruited along with Sec8 [33]. Interestingly, expression of a dominant-interfering Exo70 protein or siRNA-mediated knockdowns did not prevent GLUT4 vesicle trafficking to the plasma membrane but did inhibit GLUT4 plasma membrane fusion whereas over expression of Sec6 and Sec8 enhanced GLUT4 translocation to the plasma membrane [33,35]. Although these data indicate that the Exocyst complex plays an important role in the insulin-regulated plasma membrane docking/tethering of GLUT4 vesicles, it is well established the physiologic minimal fusion machinery is dependent upon the assembly of the SNARE complex [36][37][38] SNARE proteins can be generally classified as v-SNAREs (or R-SNAREs) that possess a single coil-coiled domain and a transmembrane domain that are localized in vesicle compartment [39][40][41][42].…”

Section: Glut4 Vesicle Docking and Plasma Membrane Fusionmentioning

confidence: 99%

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Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking

Hou

Pessin

2007

Current Opinion in Cell Biology

132

116

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SummaryGlucose transporter 4 (GLUT4) is the major insulin regulated glucose transporter expressed mainly in muscle and adipose tissue. GLUT4 is stored in a poorly characterized intracellular vesicular compartment and translocates to the cell surface in response to insulin stimulation resulting in increase glucose uptake. This process is essential for the maintenance of normal glucose homeostasis and involves a complex interplay of trafficking events and intracellular signaling cascades. Recent studies have identified sortilin as an essential element for the formation of GLUT4 storage vesicles during adipogenesis and GGA (Golgi-localized γ-ear-containing Arf-binding protein) as a key coat adaptor for the entry of newly synthesized GLUT4 into the specialized compartment. Insulinstimulated GLUT4 translocation from this compartment to the plasma membrane appears to require the Akt/protein kinase B substrate, termed AS160 (Akt Substrate of 160 kDa). In addition, the VPS9 domain-containing protein Gapex-5 in complex with CIP4 appears to function as a Rab31 guanylnucleotide exchange factor that is necessary for insulin-stimulated GLUT4 translocation. Here we attempt to summaries recent advances in GLUT4 vesicle biogenesis, intracellular trafficking and membrane fusion.

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Compartmentalization of the Exocyst Complex in Lipid Rafts Controls Glut4 Vesicle Tethering

Cited by 108 publications

References 52 publications

RalA Functions as an Indispensable Signal Mediator for the Nutrient-sensing System

RalA Functions as an Indispensable Signal Mediator for the Nutrient-sensing System

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

Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking

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