Intracellular Organization of Insulin Signaling and GLUT4 Translocation

Watson, Robert; Pessin, Jeffrey E.

doi:10.1210/rp.56.1.175

Cited by 209 publications

(166 citation statements)

References 69 publications

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“…The predominant isoforms of glucose transporters in skeletal muscle cells are GLUT 4 and GLUT 1 (35). There was no difference in the levels of GLUT 1 between control and mtDNAdepleted cells (data not shown).…”

Section: Resultsmentioning

confidence: 84%

Activation of a Novel Calcineurin-mediated Insulin-like Growth Factor-1 Receptor Pathway, Altered Metabolism, and Tumor Cell Invasion in Cells Subjected to Mitochondrial Respiratory Stress

Guha

Srinivasan

Biswas

et al. 2007

Journal of Biological Chemistry

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We have previously shown that disruption of mitochondrial membrane potential by depletion of mitochondrial DNA (mtDNA) or treatment with a mitochondrial ionophore, carbonyl cyanide m-chlorophenylhydrazone, initiates a stress signaling, which causes resistance to apoptosis, and induces invasive behavior in C2C12 myocytes and A549 cells. In the present study we show that calcineurin (Cn), activated as part of this stress signaling, plays an important role in increased glucose uptake and glycolysis. Here we report that, although both insulin and insulin-like growth factor-1 receptor levels (IR and IGF1R, respectively) are increased in response to mitochondrial stress, autophosphorylation of IGF1R was selectively increased suggesting a shift in receptor pathways. Using an approach with FK506, an inhibitor of Cn, and mRNA silencing by small interference RNA we show that mitochondrial stress-activated Cn is critical for increased GLUT 4 and IGF1R expression and activation. The importance of the IGF1R pathway in cell survival under mitochondrial stress is demonstrated by increased apoptosis either by IGF1R mRNA silencing or by treatment with IGF1R inhibitors (AG1024 and picropodophyllin). This study describes a novel mechanism of mitochondrial stress-induced metabolic shift involving Cn with implications in resistance to apoptosis and tumor proliferation.

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Section: Resultsmentioning

confidence: 84%

Activation of a Novel Calcineurin-mediated Insulin-like Growth Factor-1 Receptor Pathway, Altered Metabolism, and Tumor Cell Invasion in Cells Subjected to Mitochondrial Respiratory Stress

Guha

Srinivasan

Biswas

et al. 2007

Journal of Biological Chemistry

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“…The rationale behind the tissue-specific regulation of glucose utilization is that the brain depends almost entirely on it as an energy source. Thus a continuous supply of glucose to the brain is achieved by reducing its utilization by muscle tissue and maintaining the insulin-independent influx of glucose in neurons (42,43). The apparent importance of biotin-dependent carboxylases in brain metabolism suggests similarities between glucose and biotin utilization during nutritional deprivation.…”

Section: Biotin Availability Regulates Mrna Levels Of the Biotin Utilmentioning

confidence: 99%

Paradoxical Regulation of Biotin Utilization in Brain and Liver and Implications for Inherited Multiple Carboxylase Deficiency

Pacheco‐Alvarez

Solorzano–Vargas

Gravel

et al. 2004

Journal of Biological Chemistry

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Holocarboxylase synthetase (HCS) catalyzes the biotinylation of five carboxylases in human cells, and mutations of HCS cause multiple carboxylase deficiency (MCD). Although HCS also participates in the regulation of its own mRNA levels, the relevance of this mechanism to normal metabolism or to the MCD phenotype is not known. In this study, we show that mRNA levels of enzymes involved in biotin utilization, including HCS, are down-regulated during biotin deficiency in liver while remaining constitutively expressed in brain. We propose that this mechanism of regulation is aimed at sparing the essential function of biotin in the brain at the expense of organs such as liver and kidney during biotin deprivation. In MCD, it is possible that some of the manifestations of the disease may be associated with downregulation of biotin utilization in liver because of the impaired activity of HCS and that high dose biotin therapy may in part be important to overcoming the adverse regulatory impact in such organs.

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“…Owing to their ubiquitous presence and importance, dysfunctions of members of the MFS are related to several diseases, e.g. mutations of the D-glucose transporter (GLUT1, SLC2A1) cause the GLUT1 deficiency syndrome (Pascual et al 2004), GLUT4 (SLC2A4) mutations are associated with non-insulin-dependent diabetes mellitus (Watson & Pessin 2001), and mutations of the monocarboxylate transporter 8 (MCT8) are the underlying cause of a severe X-linked psychomotor retardation, known as the Allan-HerndonDudley syndrome (Friesema et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations

Fischer¹,

Kleinau²,

Müller³

et al. 2015

Journal of Molecular Endocrinology

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The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS). These membrane-spanning proteins facilitate translocation of a variety of substrates, MCT8 specifically transports iodothyronines. Mutations in MCT8 are the underlying cause of severe X-linked psychomotor retardation. At the molecular level, such mutations led to deficiencies in substrate translocation due to reduced cell-surface expression, impaired substrate binding, or decreased substrate translocation capabilities. However, the causal relationships between genotypes, molecular features of mutated MCT8, and patient characteristics have not yet been comprehensively deciphered. We investigated the relationship between pathogenic mutants of MCT8 and their capacity to form dimers (presumably oligomeric structures) as a potential regulatory parameter of the transport function of MCT8. Fourteen pathogenic variants of MCT8 were investigated in vitro with respect to their capacity to form oligomers. Particular mutations close to the substrate translocation channel (S194F, A224T, L434W, and R445C) were found to inhibit dimerization of MCT8. This finding is in contrast to those for other transporters or transmembrane proteins, in which substitutions predominantly at the outer-surface inhibit oligomerization. Moreover, specific mutations of MCT8 located in transmembrane helix 2 (del230F, V235M, and ins236V) increased the capacity of MCT8 variants to dimerize. We analyzed the localization of MCT8 dimers in a cellular context, demonstrating differences in MCT8 dimer formation and distribution. In summary, our results add a new link between the functions (substrate transport) and protein organization (dimerization) of MCT8, and might be of relevance for other members of the MFS. Finally, the findings are discussed in relationship to functional data combined with structural-mechanistical insights into MCT8.

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Intracellular Organization of Insulin Signaling and GLUT4 Translocation

Cited by 209 publications

References 69 publications

Activation of a Novel Calcineurin-mediated Insulin-like Growth Factor-1 Receptor Pathway, Altered Metabolism, and Tumor Cell Invasion in Cells Subjected to Mitochondrial Respiratory Stress

Activation of a Novel Calcineurin-mediated Insulin-like Growth Factor-1 Receptor Pathway, Altered Metabolism, and Tumor Cell Invasion in Cells Subjected to Mitochondrial Respiratory Stress

Paradoxical Regulation of Biotin Utilization in Brain and Liver and Implications for Inherited Multiple Carboxylase Deficiency

Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations

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