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ATM 和 GLUT1-S490 磷酸化调节骨骼肌中的 GLUT1 介导的转运。

ATM and GLUT1-S490 phosphorylation regulate GLUT1 mediated transport in skeletal muscle.

机构信息

Department of Biology, Saint Louis University, St. Louis, Missouri, United States of America.

出版信息

PLoS One. 2013 Jun 11;8(6):e66027. doi: 10.1371/journal.pone.0066027. Print 2013.

DOI:10.1371/journal.pone.0066027
PMID:23776597
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3679034/
Abstract

OBJECTIVE

The glucose and dehydroascorbic acid (DHA) transporter GLUT1 contains a phosphorylation site, S490, for ataxia telangiectasia mutated (ATM). The objective of this study was to determine whether ATM and GLUT1-S490 regulate GLUT1.

RESEARCH DESIGN AND METHODS

L6 myoblasts and mouse skeletal muscles were used to study the effects of ATM inhibition, ATM activation, and S490 mutation on GLUT1 localization, trafficking, and transport activity.

RESULTS

In myoblasts, inhibition of ATM significantly diminished cell surface GLUT1, glucose and DHA transport, GLUT1 externalization, and association of GLUT1 with Gα-interacting protein-interacting protein, C-terminus (GIPC1), which has been implicated in recycling of endosomal proteins. In contrast, ATM activation by doxorubicin (DXR) increased DHA transport, cell surface GLUT1, and the GLUT1/GIPC1 association. S490A mutation decreased glucose and DHA transport, cell surface GLUT1, and interaction of GLUT1 with GIPC1, while S490D mutation increased transport, cell surface GLUT1, and the GLUT1/GIPC1 interaction. ATM dysfunction or ATM inhibition reduced DHA transport in extensor digitorum longus (EDL) muscles and decreased glucose transport in EDL and soleus. In contrast, DXR increased DHA transport in EDL.

CONCLUSIONS

These results provide evidence that ATM and GLUT1-S490 promote cell surface GLUT1 and GLUT1-mediated transport in skeletal muscle associated with upregulation of the GLUT1/GIPC1 interaction.

摘要

目的

葡萄糖和脱氢抗坏血酸（DHA）转运蛋白 GLUT1 含有一个磷酸化位点 S490，可被共济失调毛细血管扩张症突变（ATM）磷酸化。本研究旨在确定 ATM 和 GLUT1-S490 是否调节 GLUT1。

研究设计和方法

使用 L6 成肌细胞和小鼠骨骼肌来研究 ATM 抑制、ATM 激活和 S490 突变对 GLUT1 定位、转运和转运活性的影响。

结果

在成肌细胞中，ATM 抑制显著减少细胞表面 GLUT1、葡萄糖和 DHA 转运、GLUT1 外排以及与 Gα 相互作用蛋白相互作用蛋白、C 末端（GIPC1）的 GLUT1 关联，这与内体蛋白再循环有关。相比之下，阿霉素（DXR）激活 ATM 增加了 DHA 转运、细胞表面 GLUT1 和 GLUT1/GIPC1 结合。S490A 突变降低了葡萄糖和 DHA 转运、细胞表面 GLUT1 和 GLUT1 与 GIPC1 的相互作用，而 S490D 突变增加了转运、细胞表面 GLUT1 和 GLUT1/GIPC1 的相互作用。ATM 功能障碍或 ATM 抑制减少了伸趾长肌（EDL）中的 DHA 转运，并减少了 EDL 和比目鱼肌中的葡萄糖转运。相比之下，DXR 增加了 EDL 中的 DHA 转运。

结论

这些结果提供了证据表明，ATM 和 GLUT1-S490 促进了骨骼肌细胞表面 GLUT1 和 GLUT1 介导的转运，与 GLUT1/GIPC1 相互作用的上调有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/17abd8c2b34d/pone.0066027.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/249e4aaef1d9/pone.0066027.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/a86eec1a390f/pone.0066027.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/af3f8da47247/pone.0066027.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/d475cbe67dab/pone.0066027.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/af51a3972fca/pone.0066027.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/17abd8c2b34d/pone.0066027.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/249e4aaef1d9/pone.0066027.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/a86eec1a390f/pone.0066027.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/af3f8da47247/pone.0066027.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/d475cbe67dab/pone.0066027.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/af51a3972fca/pone.0066027.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e13d/3679034/17abd8c2b34d/pone.0066027.g006.jpg

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