VAMP2, but Not VAMP3/Cellubrevin, Mediates Insulin-dependent Incorporation of GLUT4 into the Plasma Membrane of L6 Myoblasts

Randhawa, Varinder K.; Bilan, Philip J.; Khayat, Zayna A.; Daneman, Nicholas; Li, Zhi; Ramlal, Toolsie; Volchuk, Allen; Peng, Xiaorong; Coppola, Thierry; Regazzi, Romano; Trimble, William S.; Klip, Amira

doi:10.1091/mbc.11.7.2403

Cited by 102 publications

(131 citation statements)

References 60 publications

(86 reference statements)

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“…However, the response to PDGF is insensitive to cytoskeletal disruption by cytochalasin D or latrunculin B, drugs that abort the insulin response of GLUT4 (25,69). Moreover, PDGF recruits GLUT4 from the recycling endosome and involves VAMP7, whereas insulin recruits from a specialized compartment functionally characterized by VAMP2 (70,71).…”

Section: Discussionmentioning

confidence: 99%

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

Talior-Volodarsky

Randhawa

Zaid

et al. 2008

Journal of Biological Chemistry

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Insulin induces GLUT4 translocation to the muscle cell surface. Using differential amino acid labeling and mass spectrometry, we observed insulin-dependent co-precipitation of actinin-4 (ACTN4) with GLUT4 (Foster, L. J., Rudich, A., Talior, I., Patel, N., Huang, X., Furtado, L. M., Bilan, P. J., Mann, M., and Klip, A. (2006) J. Proteome Res. 5, 64 -75). ACTN4 links F-actin to membrane proteins, and actin dynamics are essential for GLUT4 translocation. We hypothesized that ACTN4 may contribute to insulin-regulated GLUT4 traffic. In L6 muscle cells insulin, but not platelet-derived growth factor, increased co-precipitation of ACTN4 with GLUT4. Small interfering RNA-mediated ACTN4 knockdown abolished the gain in surface-exposed GLUT4 elicited by insulin but not by platelet-derived growth factor, membrane depolarization, or mitochondrial uncoupling. In contrast, knockdown of ␣-actinin-1 (ACTN1) did not prevent GLUT4 translocation by insulin. GLUT4 colocalized with ACTN4 along the insulin-induced cortical actin mesh and ACTN4 knockdown prevented GLUT4-actin colocalization without impeding actin remodeling or Akt phosphorylation, maintaining GLUT4 in a tight perinuclear location. We propose that ACTN4 contributes to GLUT4 traffic, likely by tethering GLUT4 vesicles to the cortical actin cytoskeleton. Insulin-regulated glucose transporter 4 (GLUT4)4 is a member of the SLC2A facilitative glucose transporter family (2) and is responsible for glucose entry into muscle and fat tissues (3-5). GLUT4 continuously cycles to/from the cell membrane through a series of endosomal compartments. In response to insulin there is a rapid increase in the steady-state level of GLUT4 at the cell surface, at the expense of intracellular pools (6 -9). This process is defective in insulin resistance and type 2 diabetes (10 -12). Stimuli other than insulin such as muscle contraction, depolarization, or hypoxia also increase surface GLUT4 (13-16). Whereas insulin largely increases the exocytic arm of GLUT4 cycling (17), hypoxia or membrane depolarization preferentially reduce GLUT4 endocytosis in muscle cells (16,18,19). Moreover, although insulin-dependent GLUT4 translocation requires dynamic remodeling of filamentous actin (20 -23), the gain in surface GLUT4 elicited by plateletderived growth factor (PDGF), depolarization, or mitochondrial uncouplers is independent of actin dynamics (24 -26).Intensive research has recently focused on identifying the individual mechanisms participating in GLUT4 traffic and the specific events regulated by insulin (27)(28)(29)(30)(31). Hypothesizing that GLUT4 traffic may be regulated by interaction with partner proteins, it is of fundamental and clinical interest to identify such proteins. Accordingly, we recently applied the novel SILAC (stable isotope labeling by amino acids in cell culture) approach (32) to search for proteins that associate with GLUT4 in an insulin-regulated manner (1). The study took advantage of the stable expression in L6 muscle cells of GLUT4 encoding an myc tag that faces the extrace...

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Section: Discussionmentioning

confidence: 99%

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

Talior-Volodarsky

Randhawa

Zaid

et al. 2008

Journal of Biological Chemistry

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“…The use of various proteolytic toxins and dominant-interfering mutants has demonstrated that VAMP2 is the predominant v-SNARE required for insulin-stimulated GLUT4 translocation [45,46]. Interestingly, although VAMP2 is essential for insulin-stimulated GLUT4 translocation is completely dispensable for other signals inducing GLUT4 translocation, such as osmotic shock.…”

Section: Glut4 Vesicle Docking and Plasma Membrane Fusionmentioning

confidence: 99%

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

Hou

Pessin

2007

Current Opinion in Cell Biology

130

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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“…Similar to syntaxin 1, syntaxin 4 localizes at the plasma membrane and provides the binding site for numerous proteins including VAMP2/3, SNAP23, Munc 18c, Synip (syntaxin4 interacting protein), synaptotagmin, and most recently Rab4 [142,144,[146][147][148][149][150][151][152][153]. GLUT4 vesicles contain both VAMP2 and VAMP3 v-SNAREs.…”

Section: Snare Proteins Controlling Glut4 Traffickingmentioning

confidence: 99%

“…First, specific cleavage of VAMP2 with neurotoxin D, inhibited insulin-stimulated GLUT4 translocation [146]. Second, this inhibition was rescued by overexpression of a toxin-resistant VAMP2 mutant but a toxin-resistant VAMP3 protein [150]. Third, in compartment ablation experiments, disruption of the VAMP3/transferrin receptor positive had only a small effect on insulin-stimulated GLUT4 translocation and VAMP2 levels [154].…”

Section: Snare Proteins Controlling Glut4 Traffickingmentioning

confidence: 99%

An adipocentric view of signaling and intracellular trafficking

Mora

Pessin

2002

Diabetes Metabolism Res

148

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SummaryAdipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-α, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter.

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VAMP2, but Not VAMP3/Cellubrevin, Mediates Insulin-dependent Incorporation of GLUT4 into the Plasma Membrane of L6 Myoblasts

Cited by 102 publications

References 60 publications

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

α-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation

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

An adipocentric view of signaling and intracellular trafficking

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