The Amino Terminus of Insulin-responsive Aminopeptidase Causes Glut4 Translocation in 3T3-L1 Adipocytes

Waters, Steven B.; D'Auria, Matt; Martin, Stuart S.; Nguyen, Chris; Kozma, Lynn M.; Luskey, Kenneth L.

doi:10.1074/jbc.272.37.23323

Cited by 112 publications

(105 citation statements)

References 25 publications

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“…This model is consistent with the predominant localization of GLUT4 predominantly in tubulo-vesicular elements beneath the plasma membrane, with the remaining protein found in the trans-Golgi network, clathrin-coated vesicles, and endosome structures (49,50). In addition, the cytoplasmic domain of IRAP/vp165 and the carboxyl-terminal domain of GLUT4 appear to provide retention information and disruption of this signal results in plasma membrane translocation (42,51,52). Alternatively, a substantial proportion of the GLUT4-containing vesicles appear to be segregated away from recycling endosome markers, having characteristics analogous to small synaptic vesicles.…”

Section: Discussionsupporting

confidence: 59%

Regulation of Insulin-stimulated GLUT4 Translocation by Munc18c in 3T3L1 Adipocytes

Thurmond¹,

Ceresa²,

Okada

et al. 1998

Journal of Biological Chemistry

216

237

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Insulin stimulates glucose transporter (GLUT) 4 vesicle translocation from intracellular storage sites to the plasma membrane in 3T3L1 adipocytes through a VAMP2-and syntaxin 4-dependent mechanism. We have observed that Munc18c, a mammalian homolog of the yeast syntaxin-binding protein n-Sec1p, competed for the binding of VAMP2 to syntaxin 4. Consistent with an inhibitory function for Munc18c, expression of Munc18c, but not the related Munc18b isoform, prevented the insulin stimulation of GLUT4 and IRAP/vp165 translocation to the plasma membrane without any significant effect on GLUT1 trafficking. As expected, overexpressed Munc18c was found to co-immunoprecipitate with syntaxin 4 in the basal state. However, these complexes were found to dissociate upon insulin stimulation. Furthermore, endogenous Munc18c was predominantly localized to the plasma membrane and its distribution was not altered by insulin stimulation. Although expression of enhanced green fluorescent protein-Munc18c primarily resulted in a dispersed cytosolic distribution, co-expression with syntaxin 4 resulted in increased localization to the plasma membrane. Together, these data suggest that Munc18c inhibits the docking/fusion of GLUT4-containing vesicles by blocking the binding of VAMP2 to syntaxin 4. Insulin relieves this inhibition by inducing the dissociation of Munc18c from syntaxin 4 and by sequestering Munc18c to an alternative plasma membrane binding site.The binding of insulin to its heterotetrameric integral-membrane receptor activates its intracellular tyrosine kinase domain and thereby triggers a signaling cascade resulting in the translocation and fusion of intracellular GLUT4 1 isoform-containing vesicles to the plasma membrane (1-3). Although most cell types also constitutively express the GLUT1 isoform at the cell surface, the insulin-stimulated increase in plasma membrane-associated GLUT4 protein accounts for the majority of post-prandial glucose disposal in both muscle and adipose tissue (4).The insulin-stimulated translocation of these GLUT4-containing vesicles has several features in common with the regulated exocytosis pathway of synaptic vesicle trafficking in neurotransmitter release (5). The machinery involved in the regulation of synaptic vesicle priming/docking/fusion entails the pairing of protein complexes in the vesicle compartment (v-SNAREs, for vesicle SNAP receptors) with their cognate receptor complexes at the target membrane (t-SNAREs, for target membrane SNAP receptors). Recently, several of the vand t-SNARE proteins have been identified that specifically participate in the insulin-regulated docking and fusion of GLUT4 vesicles with the adipocyte plasma membrane. GLUT4 vesicles co-purify with both the VAMP2 and VAMP3 v-SNARE isoforms and specific proteolytic cleavage of VAMP2, expression of a dominant-interfering VAMP2 mutant or inhibitory peptides impairs insulin-stimulated GLUT4 translocation (6 -11). In addition, transferrin-horseradish peroxidase ablation of recycling endosomes resulted in a selective loss ...

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Section: Discussionsupporting

confidence: 59%

Regulation of Insulin-stimulated GLUT4 Translocation by Munc18c in 3T3L1 Adipocytes

Thurmond¹,

Ceresa²,

Okada

et al. 1998

Journal of Biological Chemistry

216

237

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“…We speculate that the formation of a TUG-ACBD3 complex in unstimulated adipocytes may play some role in fatty acid metabolism. Acyl-CoA dehydrogenases have been identified on GLUT4 vesicles and bind IRAP at a site that is critical for GLUT4 intracellular retention (50,51). The long chain fatty acyl CoA synthetase ACSL1 was also found in association with TUG 6 and sortilin (52) and may function in GSV biogenesis or retention.…”

Section: Discussionmentioning

confidence: 99%

Acetylation of TUG Protein Promotes the Accumulation of GLUT4 Glucose Transporters in an Insulin-responsive Intracellular Compartment

Belman

Bian²,

Habtemichael³

et al. 2015

Journal of Biological Chemistry

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Background: Insulin stimulates glucose uptake by triggering TUG proteolysis, which liberates intracellular storage vesicles containing GLUT4. Results: TUG acetylation modulates its interaction with Golgi matrix proteins and enhances its function to trap GLUT4 storage vesicles within unstimulated cells. SIRT2 modulates TUG acetylation and controls insulin sensitivity in vivo. Conclusion: TUG acetylation promotes GLUT4 accumulation in insulin-responsive vesicles. Significance: Nutritional status modulates insulin-stimulated glucose uptake.

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“…In fact, it is more abundantly expressed in vesicles than the transporter (Kupriyanova et al, 2002). When the cytoplasmic N-terminus of IRAP was microinjected into 3T3-L1 adipocytes, GLUT4 was localized on the plasma membrane even in the basal state (Waters et al, 1997), suggesting IRAP can play a role in GSV movement/targeting. A chimeric protein containing the intracellular domain of IRAP and the extracellular and transmembrane domains of the transferrin receptor displays IRAP-and GLUT4-like trafficking in 3T3-L1 adipocytes (Subtil et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

Hosaka

Brooks

Presman

et al. 2005

MBoC

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Insulin-regulated aminopeptidase (IRAP) is an abundant cargo protein of Glut4 storage vesicles (GSVs) that traffics to and from the plasma membrane in response to insulin. We used the amino terminus cytoplasmic domain of IRAP, residues 1-109, as an affinity reagent to identify cytosolic proteins that might be involved in GSV trafficking. In this way, we identified p115, a peripheral membrane protein known to be involved in membrane trafficking. In murine adipocytes, we determined that p115 was localized to the perinuclear region by immunofluorescence and throughout the cell by fractionation. By immunofluorescence, p115 partially colocalizes with GLUT4 and IRAP in the perinuclear region of cultured fat cells. The amino terminus of p115 binds to IRAP and overexpression of a N-terminal construct results in its colocalization with GLUT4 throughout the cell. Insulin-stimulated GLUT4 translocation is completely inhibited under these conditions. Overexpression of p115 C-terminus has no significant effect on GLUT4 distribution and translocation. Finally, expression of the p115 N-terminus construct has no effect on the distribution and trafficking of GLUT1. These data suggest that p115 has an important and specific role in insulin-stimulated Glut4 translocation, probably by way of tethering insulin-sensitive Glut4 vesicles at an as yet unknown intracellular site. INTRODUCTIONInsulin normalizes blood glucose levels by mobilizing the muscle and adipocyte glucose transporter isoform, GLUT4, from intracellular storage vesicles and moving it to the plasma membrane (Simpson et al., 2001;Bryant et al., 2002). Various models of GLUT4 trafficking suggest that GLUT4 must exist in more than one intracellular compartment and the major insulin sensitive pool is localized to a compartment that is distinct from endosomal markers and is commonly referred to as glucose transporter storage vesicles (GSVs), or insulin responsive vesicle (IRVs). Despite the critical function of glucose transport in glucose homeostasis, many of the details by which adipocytes and muscle form a pathway of insulin-sensitive GLUT4 trafficking remain unknown. However, it is virtually certain that the major cargo proteins of GSVs must interact with a number of cytosolic and membrane proteins, such as adaptors and tethers, in order to be properly sorted and regulated by insulin.Insulin-responsive aminopeptidase (IRAP) was identified as an abundant cargo protein associated with GLUT4 vesicles that translocates in response to insulin in a manner seemingly identical to GLUT4 Mastick et al., 1994;Keller et al., 1995;Malide et al., 1997;Martin et al., 1997;Ross et al., 1997). In fact, it is more abundantly expressed in vesicles than the transporter (Kupriyanova et al., 2002). When the cytoplasmic N-terminus of IRAP was microinjected into 3T3-L1 adipocytes, GLUT4 was localized on the plasma membrane even in the basal state (Waters et al., 1997), suggesting IRAP can play a role in GSV movement/targeting. A chimeric protein containing the intracellular domain of IRAP and ...

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The Amino Terminus of Insulin-responsive Aminopeptidase Causes Glut4 Translocation in 3T3-L1 Adipocytes

Cited by 112 publications

References 25 publications

Regulation of Insulin-stimulated GLUT4 Translocation by Munc18c in 3T3L1 Adipocytes

Regulation of Insulin-stimulated GLUT4 Translocation by Munc18c in 3T3L1 Adipocytes

Acetylation of TUG Protein Promotes the Accumulation of GLUT4 Glucose Transporters in an Insulin-responsive Intracellular Compartment

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

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