β-catenin is important for the development of an insulin responsive pool of GLUT4 glucose transporters in 3T3-L1 adipocytes

Dissanayake, Waruni C.; Sorrenson, Brie; Cognard, Emmanuelle; Hughes, William E.; Shepherd, Peter R.

doi:10.1016/j.yexcr.2018.03.011

Cited by 18 publications

(22 citation statements)

References 33 publications

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“…Importantly, we provide evidence that the serine 552 phosphorylation site of β-catenin is involved in regulating insulin-induced GLUT4 membrane recruitment by interacting with muscle specific cell adhesion molecule M-cadherin to support insulin-mediated cortical actin remodelling. This is consistent with recent evidence that β-catenin is a regulator of GLUT4 trafficking in 3T3-L1 adipocytes [ 17 ] and acts as a signalling intermediate controlling vesicle movement across multiple tissues [ 28 , [45] , [46] , [47] ].…”

Section: Discussionsupporting

confidence: 92%

“…Canonically, β-catenin is best recognised as the downstream effector of Wnt signalling, in which levels of β-catenin are regulated by a Wnt ligand-inhibited degradation complex, leading to accumulation of the protein and activation of Wnt target genes [ 14 , 15 ]. However, it has been identified in cross-species screens as a candidate gene involved in the development of insulin-resistance [ 16 ] and also implicated in the regulation of GLUT4 trafficking in adipocytes [ 17 ]. Many of the proteins involved in insulin signalling, including Akt, PAK1 and Rac1, are known to modulate β-catenin function in non-muscle cells, as well as insulin-induced actin remodelling [ 4 , [18] , [19] , [20] ].…”

Section: Introductionmentioning

confidence: 99%

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β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

Masson

Sorrenson

Shepherd

et al. 2020

Molecular Metabolism

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Objective Skeletal muscle glucose disposal following a meal is mediated through insulin-stimulated movement of the GLUT4-containing vesicles to the cell surface. The highly conserved scaffold-protein β-catenin is an emerging regulator of vesicle trafficking in other tissues. Here, we investigated the involvement of β-catenin in skeletal muscle insulin-stimulated glucose transport. Methods Glucose homeostasis and transport was investigated in inducible muscle specific β-catenin knockout (BCAT-mKO) mice. The effect of β-catenin deletion and mutation of β-catenin serine 552 on signal transduction, glucose uptake and protein–protein interactions were determined in L6-G4-myc cells, and β-catenin insulin-responsive binding partners were identified via immunoprecipitation coupled to label-free proteomics. Results Skeletal muscle specific deletion of β-catenin impaired whole-body insulin sensitivity and insulin-stimulated glucose uptake into muscle independent of canonical Wnt signalling. In response to insulin, β-catenin was phosphorylated at serine 552 in an Akt-dependent manner, and in L6-G4-myc cells, mutation of β-catenin S552 impaired insulin-induced actin-polymerisation, resulting in attenuated insulin-induced glucose transport and GLUT4 translocation. β-catenin was found to interact with M-cadherin in an insulin-dependent β-catenin S552 -phosphorylation dependent manner, and loss of M-cadherin in L6-G4-myc cells attenuated insulin-induced actin-polymerisation and glucose transport. Conclusions Our data suggest that β-catenin is a novel mediator of glucose transport in skeletal muscle and may contribute to insulin-induced actin-cytoskeleton remodelling to support GLUT4 translocation.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

Masson

Sorrenson

Shepherd

et al. 2020

Molecular Metabolism

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“…It was part of a human skeletal muscle gene expression signature that was diagnostic for insulin resistance and inhibition of ␤-catenin inhibited insulin-stimulated glucose uptake in L6 myotubes (52) and in 3T3-L1 adipocytes (53). Consistent with a role for ␤-catenin in insulin sensitivity, drug-induced ␤-catenin stabilization enhances insulin-mediated glucose uptake in adipocytes (53). As ␤-catenin stabilization also occurs as a consequence of tankyrase activity (25), it is conceivable that tankyrase activation, which reportedly occurs in response to insulin (19), may in fact enhance insulin sensitivity.…”

Section: Tankyrase Regulation Of Insulin Sensitivitymentioning

confidence: 83%

Tankyrase modulates insulin sensitivity in skeletal muscle cells by regulating the stability of GLUT4 vesicle proteins

Deshpande

James

et al. 2018

Journal of Biological Chemistry

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Tankyrase 1 and 2, members of the poly(ADP-ribose) polymerase family, have previously been shown to play a role in insulin-mediated glucose uptake in adipocytes. However, their precise mechanism of action, and their role in insulin action in other cell types, such as myocytes, remains elusive. Treatment of differentiated L6 myotubes with the small molecule tankyrase inhibitor XAV939 resulted in insulin resistance as determined by impaired insulin-stimulated glucose uptake. Proteomic analysis of XAV939-treated myotubes identified down-regulation of several glucose transporter GLUT4 storage vesicle (GSV) proteins including RAB10, VAMP8, SORT1, and GLUT4. A similar effect was observed following knockdown of tankyrase 1 in L6 myotubes. Inhibition of the proteasome using MG132 rescued GSV protein levels as well as insulin-stimulated glucose uptake in XAV939-treated L6 myotubes. These studies reveal an important role for tankyrase in maintaining the stability of key GLUT4 regulatory proteins that in turn plays a role in regulating cellular insulin sensitivity.

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“…Adherens junctions play an important role in the regulation of some vesicle trafficking processes, including GSIS [5,18,21,22]. β-catenin mediates some effects of adherens junctions [23] and we have previously shown its is required for the proper translocation of GLUT4 containing vesicles in adipocytes [21] and of insulin containing vesicles in β-cells [18].…”

Section: Discussionmentioning

confidence: 96%

α-catenin isoforms are regulated by glucose and involved in regulating insulin secretion in rat clonal β-cell models

Dissanayake

Sorrenson

Lee

et al. 2020

Biochemical Journal

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The recent finding that β-catenin levels play an important rate-limiting role in processes regulating insulin secretion lead us to investigate whether its binding partner α-catenin also plays a role in this process. We find that levels of both α-E-catenin and α-N-catenin are rapidly up-regulated as levels of glucose are increased in rat clonal β-cell models INS-1E and INS-832/3. Lowering in levels of either α-catenin isoform using siRNA resulted in significant increases in glucose stimulated insulin secretion (GSIS) and this effect was attenuated when β-catenin levels were lowered indicating these proteins have opposing effects on insulin release. This effect of α-catenin knockdown on GSIS was not due to increases in insulin expression but was associated with increases in calcium influx into cells. Moreover, simultaneous depletion of α-E catenin and α-N catenin decreased the actin polymerisation to a similar degree as latrunculin treatment and inhibition of ARP 2/3 mediated actin branching with CK666 attenuated the α-catenin depletion effect on GSIS. This suggests α-catenin mediated actin remodelling may be involved in the regulation of insulin secretion. Together this indicates that α-catenin and β-catenin can play opposing roles in regulating insulin secretion, with some degree of functional redundancy in roles of α-E-catenin and α-N-catenin. The finding that, at least in β-cell models, the levels of each can be regulated in the longer term by glucose also provides a potential mechanism by which sustained changes in glucose levels might impact on the magnitude of GSIS.

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β-catenin is important for the development of an insulin responsive pool of GLUT4 glucose transporters in 3T3-L1 adipocytes

Cited by 18 publications

References 33 publications

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

Tankyrase modulates insulin sensitivity in skeletal muscle cells by regulating the stability of GLUT4 vesicle proteins

α-catenin isoforms are regulated by glucose and involved in regulating insulin secretion in rat clonal β-cell models

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