Identification of a novel AS160 splice variant that regulates GLUT4 translocation and glucose-uptake in rat muscle cells

Baus, Daniela; Heermeier, Kathrin; Hoop, Meltsje de; Metz-Weidmann, Christiane; Gassenhuber, Johann; Dittrich, Winand H.; Welte, S.; Tennagels, Norbert

doi:10.1016/j.cellsig.2008.08.010

Cited by 42 publications

(36 citation statements)

References 34 publications

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“…The predominant PCR product amplified from the MM cell line cDNA was significantly shorter than the product from the vector; consistent with the 189 bp length of exons 11 and 12 (Figure 1B). Sequencing of the PCR products confirmed the absence of exons 11 and 12 [5]. Furthermore, RNA-Seq transcriptomic analysis of the JJN3 myeloma cell line confirmed complete sequence identity with the AS160_v2 reference sequence [5].…”

Section: Resultsmentioning

confidence: 94%

“…Interestingly, a novel AS160 splice variant was recently discovered (termed AS160_v2 or AS160 variant 2) which lacks exons 11 and 12 and exhibits a broad expression profile in human tissues [5]. The lack of these coding sequences appears to imbue the AS160_v2 protein with an increased permissiveness toward GLUT4 trafficking to the cell surface without the exclusion of any known phosphorylation sites or protein subdomains [5].…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…The lack of these coding sequences appears to imbue the AS160_v2 protein with an increased permissiveness toward GLUT4 trafficking to the cell surface without the exclusion of any known phosphorylation sites or protein subdomains [5]. Importantly, it has been demonstrated that ectopic expression of AS160_v2 in rat L6 myotubes enhances GLUT4 PM localization and increases glucose consumption rates by 30% to 40% during insulin or IGF-1 treatment [5]. Given the importance of AS160 in the regulation of GLUT4 trafficking, the identification of a splice variant of AS160 displaying a diminished propensity for GLUT4 retention, and the knowledge that the AGC kinases AKT [6], RSK [7], and SGK [8] are constitutively active in myeloma, we sought to determine whether AS160 deregulation contributes substantively to the basal activation of GLUT4, that we have previously demonstrated in myeloma cells [9].…”

Section: Resultsmentioning

confidence: 99%

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Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma

et al. 2013

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BackgroundMultiple myeloma (MM) is a fatal plasma cell malignancy exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e., the Warburg effect). We have previously demonstrated that myeloma cells exhibit constitutive plasma membrane (PM) localization of GLUT4, consistent with the dependence of MM cells on this transporter for maintenance of glucose consumption rates, proliferative capacity, and viability. The purpose of this study was to investigate the molecular basis of constitutive GLUT4 plasma membrane localization in MM cells.FindingsWe have elucidated a novel mechanism through which myeloma cells achieve constitutive GLUT4 activation involving elevated expression of the Rab-GTPase activating protein AS160_v2 splice variant to promote the Warburg effect. AS160_v2-positive MM cell lines display constitutive Thr642 phosphorylation, known to be required for inactivation of AS160 Rab-GAP activity. Importantly, we show that enforced expression of AS160_v2 is required for GLUT4 PM translocation and activation in these select MM lines. Furthermore, we demonstrate that ectopic expression of a full-length, phospho-deficient AS160 mutant is sufficient to impair constitutive GLUT4 cell surface residence, which is characteristic of MM cells.ConclusionsThis is the first study to tie AS160 de-regulation to increased glucose consumption rates and the Warburg effect in cancer. Future studies investigating connections between the insulin/IGF-1/AS160_v2/GLUT4 axis and FDG-PET positivity in myeloma patients are warranted and could provide rationale for therapeutically targeting this pathway in MM patients with advanced disease.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma

et al. 2013

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“…The nature of the low molecular weight forms of TBC1D4 is unclear and may represent splice variants. Alternative splicing of the TBC1D4 gene has been described (Baus et al 2008). Likewise, the ENSEMBL database (http://www.ensembl.org) lists seven different TBC1D4 transcripts.…”

Section: Characterization Of the Tbc1d4 Antibodymentioning

confidence: 99%

Immunofluorescent localization of the Rab-GAP protein TBC1D4 (AS160) in mouse kidney

Lier

Gresko

Chiara

et al. 2012

Histochem Cell Biol

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TBC1D4 (or AS160) was identified as a Rab-GTPase activating protein (Rab-GAP) that controls insulin-dependent trafficking of the glucose transporter GLUT4 in skeletal muscle cells and in adipocytes. Recent in vitro cell culture studies suggest that TBC1D4 may also regulate the intracellular trafficking of kidney proteins such as the vasopressin-dependent water channel AQP2, the aldosterone-regulated epithelial sodium channel ENaC, and the Na(+)-K(+)-ATPase. To study the possible role of TBC1D4 in the kidney in vivo, we raised a rabbit polyclonal antibody against TBC1D4 to be used for immunoblotting and immunohistochemical studies. In immunoblots on mouse kidney homogenates, the antibody recognizes specific bands at the expected size of 160 kDa and at lower molecular weights, which are absent in kidneys of TBC1D4 deficient mice. Using a variety of nephron-segment-specific marker proteins, immunohistochemistry reveals TBC1D4 in the cytoplasm of the parietal epithelial cells of Bowman's capsule, the thin and thick limbs of Henle's loop, the distal convoluted tubule, the connecting tubule, and the collecting duct. In the latter, both principal as well as intercalated cells are TBC1D4-positive. Thus, with the exception of the proximal tubule, TBC1D4 is highly expressed along the nephron and the collecting duct, where it may interfere with the intracellular trafficking of many renal transport proteins including AQP2, ENaC and Na(+)-K(+)-ATPase. Hence, TBC1D4 may play an important role for the control of renal ion and water handling and hence for the control of extracellular fluid homeostasis.

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Assays for Insulin and Insulin-Like Activity Based on Adipocytes

Müller¹

2016

Drug Discovery and Evaluation: Pharmacological Assays

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Identification of a novel AS160 splice variant that regulates GLUT4 translocation and glucose-uptake in rat muscle cells

Cited by 42 publications

References 34 publications

Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma

Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma

Immunofluorescent localization of the Rab-GAP protein TBC1D4 (AS160) in mouse kidney

Assays for Insulin and Insulin-Like Activity Based on Adipocytes

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