Potential Role of Rab4 in the Regulation of Subcellular Localization of Glut4 in Adipocytes

Cormont, Mireille; Bortoluzzi, Marie-Noëlle; Gautier, Nadine; Mari, Muriel; Obberghen, Emmanuel Van; Marchand-Brustel, Y. Le

doi:10.1128/mcb.16.12.6879

Cited by 101 publications

(96 citation statements)

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“…Rab4 also regulates exocytic events from other post-Golgi compartments in cells with specialized functions (34). In adipocytes, Rab4 controls recycling of the insulin-regulated glucose transporter GLUT4 (37), and recombinant Rab4 stimulates ␣-granule secretion in platelets in vitro (38). All Rab proteins contain highly conserved domains required for guanine nucleotide binding, GTP/GDP exchange, and GTP hydrolysis that are essential for their proper targeting and function (31).…”

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confidence: 99%

Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Ahmed

Jeffus

Bukhari

et al. 2008

Journal of Biological Chemistry

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The serotonin transporter (SERT) on the plasma membrane is the major mechanism for the clearance of plasma serotonin (5-hydroxytryptamine (5HT)). The uptake rates of cells depend on the density of SERT molecules on the plasma membrane. Interestingly, the number of SERT molecules on the platelet surface is down-regulated when plasma 5HT ([5HT] ex ) is elevated. It is well reported that stimulation of cells with high [5HT] ex induces transamidation of a small GTPase, Rab4. Modification with 5HT stabilizes Rab4 in its active, GTP-bound form, Rab4-GTP. Although investigating the mechanism by which elevated plasma 5HT level down-regulates the density of SERT molecules on the plasma membrane, we studied Rab4 and SERT in heterologous and platelet expression systems. Our data demonstrate that, in response to elevated [5HT] ex , Rab4-GTP co-localizes with and binds to SERT. The association of SERT with Rab4-GTP depends on: (i) 5HT modification and (ii) the GTP-binding ability of Rab4. Their association retains transporter molecules intracellularly. Furthermore, we mapped the Rab4-SERT association domain to amino acids 616 -624 in the cytoplasmic tail of SERT. This finding provides an explanation for the role of the C terminus in the localization and trafficking of SERT via Rab4 in a plasma 5HT-dependent manner. Therefore, we propose that elevated [5HT] ex "paralyzes" the translocation of SERT from intracellular locations to the plasma membrane by controlling transamidation and Rab4-GTP formation.The serotonin transporter (SERT) 2 is a member of the Cl Ϫ -and Na ϩ -dependent monoamine transporter family, which also includes the dopamine transporter (DAT) and the norepinephrine transporter. SERT is a 630-amino acid plasma membrane-bound glycoprotein. Hydropathy analysis predicts that SERT contains 12 transmembrane domains and that both the N and C termini are exposed to the cytoplasm. The primary function of SERT in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin (5-hydroxytryptamine (5HT)) molecules from the synaptic cleft into the pre-synaptic terminal for re-utilization. SERT is also expressed in non-neuronal cells, including platelets, placental, intestinal and adrenal cell lines, but the exact function of SERT in these cell lines is still under investigation (1-5).The C-and N-terminal regions of monoamine transporter proteins have just recently garnered increased attention for their importance in transport function and localization. Significant work has been accomplished in identifying the importance of the C-terminal region of DAT and norepinephrine transporter in transporter function, expression, and localization (6 -9).The proteins interacting with the N terminus of SERT are syntaxin 1A (10, 11) and secretory carrier membrane protein 2 (12). SERT also complexes with Hic-5 (13) and ␣-synuclein (14), but the functional significance of these interactions are not known. PICK1 (15), MacMARCKS (16), the actin cytoskeleton (49), neuronal nitric-oxide synthase, and Se...

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Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Ahmed

Jeffus

Bukhari

et al. 2008

Journal of Biological Chemistry

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“…Earlier studies supported the notion that small GTP-binding proteins are also involved in the trafficking of GLUT4 [21,37] but only Rab4 has been identified as being associated with GLUT4-containing vesicles [15] and functionally related to GLUT4 translocation [18,19] in both adipocytes and myocytes. We now report that in addition to Rab4, Rab11 co-localizes with GLUT4 in the basal state.…”

Section: Discussionmentioning

confidence: 70%

“…We therefore suggest that at least two members of the Rab family, Rab4 and Rab11, participate in GLUT4 trafficking and that these proteins exert different functions. This notion would fit to a model in which Rab4 mediates the endocytosis of GLUT4 [18,19,20], whereas Rab11 participates in the insulin-regulated exocytosis and sorting of the transporter from the endosomal/recycling compartment. Several lines of evidence support this assumption.…”

Section: Discussionmentioning

confidence: 99%

“…Further, microinjection of Rab4 antibodies [16] and peptides against the hypervariable carboxy-terminal domain [17] were shown to inhibit insulin-induced GLUT4 translocation. Functional implication of Rab4 in GLUT4 trafficking was recently confirmed by overexpression in adipocytes [18] and myocytes [19] and by heterologous expression of Rab4 and GLUT4 in Xenopus oocytes [20]. These studies showed, however, that Rab4 participates in the intracellular sequestration of GLUT4 and the biogenesis of the GLUT4 storage compartment but most probably not in the exocytotic movement to the plasma membrane [18,19].…”

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Rab11 is associated with GLUT4-containing vesicles and redistributes in response to insulin

et al. 2000

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Homeostasis of blood glucose by insulin involves the rapid and large stimulation of glucose uptake by muscle and adipose tissue. This important action of the hormone is based on the translocation of the glucose transporter isoform GLUT4 from an intracellular pool to the cell surface [1,2]. A major aspect of this process that is still to be defined is that of the downstream signalling from the insulin receptor to the GLUT4 compartment and how these signals trigger recruitment of the GLUT4-containing vesicles to the plasma membrane. To explain these processes, several laboratories have isolated the intracellular vesicles containing GLUT4 and characterized their protein composition [3±9]. In addition to GLUT4, three major companion proteins have been identified in GLUT4-containing vesicles including an insulin-reg- Diabetologia (2000) Abstract Aims/hypothesis. To identify a GTPase of 24 000 M r which we recently found to co-localize with GLUT4 in cardiac muscle. Methods. A 24 000 M r -GTP-binding fraction was purified from pig heart by a three-step chromatographic procedure, followed by two-dimensional electrophoresis and electrospray ionization-mass spectrometry. Subcellular distribution of the GTPase was assessed by western blotting. Co-localization with GLUT4 was assessed by continuous sucrose density gradient fractionation and immunoadsorption of GLUT4-containing vesicles.Results. The Rab11 protein was identified as a major component of the GTP-binding fraction and its expression in rat cardiac muscle was confirmed. In vivo insulin treatment resulted in the recruitment of Rab11 from the microsomal fraction to the plasma membrane. Subcellular fractionation indicated two immunoreactive GLUT4 pools. Most of the intracellular pool of Rab11 overlapped with the high-density GLUT4 pool and most of the transferrin receptor pool. The Rab11 protein also co-sedimented with the low-density, non-endosomal GLUT4 pool and substantially increased in this fraction after insulin treatment. It was specifically present in GLUT4-containing vesicles and insulin increased its abundance in these vesicles 2.2-fold relative to the amount of GLUT4. These vesicles also containend Rab4 and Akt-2, the latter being only associated after insulin stimulation. Insulin was unable to alter the cellular localization of Rab11 in insulin-resistant obese Zucker rats. Conclusion/interpretation. These results support the hypothesis that at least two GTPases of the Rab family participate in GLUT4-vesicle trafficking. We suggest that Rab11 is involved in the endosomal recycling, sorting and exocytotic movement of the glucose transporter.

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“…In mammalian cells, there are more than 50 different rab GTPases described that are localized to different subcellular compartments with distinct regulatory functions mediating specific membrane traffic steps (for reviews see References [159][160][161][162]). Among this large family, Rab4 has been shown to associate with GLUT4 containing vesicles and implicated in insulin action in adipocytes [163,164]. Rab4 appears to undergo an insulin-stimulated redistribution from GLUT4 vesicles to the cytosol, where it associates with the GDP-dissociation inhibitor GDI-I [153,165].…”

Section: Other Modulators Of Glut4 Traffickingmentioning

confidence: 99%

An adipocentric view of signaling and intracellular trafficking

Mora

Pessin

2002

Diabetes Metabolism Res

149

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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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Potential Role of Rab4 in the Regulation of Subcellular Localization of Glut4 in Adipocytes

Cited by 101 publications

References 56 publications

Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Rab11 is associated with GLUT4-containing vesicles and redistributes in response to insulin

An adipocentric view of signaling and intracellular trafficking

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