A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression
A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression
复制标题
DOI：
10.1152/ajpcell.00554.2007
复制
发表时间：
2008-09-01
影响因子：
5.5
通讯作者：
Brosius, Frank C., III
中科院分区：
文献类型：
--
作者：
Buller, Carolyn L.;Loberg, Robert D.;Brosius, Frank C., III
葡萄糖转运是一个高度调节的过程，并依赖于各种信号事件。糖原合成酶激酶-3（GSK-3）参与葡萄糖转运调节的各个方面，但GSK-3活性影响葡萄糖摄取的机制尚未明确。我们报告说，基础糖原合成酶激酶-3（GSK-3）的活性调节葡萄糖转运在几种细胞类型。在几种细胞类型（包括血管平滑肌细胞）中长期抑制基础GSK-3活性（8-24 h），由于促进性葡萄糖转运蛋白1（GLUT 1）的蛋白表达类似增加，导致葡萄糖摄取增加约两倍。相反，GSK-3 β的组成型活性形式的表达导致GLUT 1表达和葡萄糖摄取至少降低两倍。由于GSK-3可以通过结节性硬化症复合体亚单位2（TSC 2）肿瘤抑制因子的磷酸化来抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号传导，因此我们研究了GSK-3对葡萄糖摄取和GLUT 1表达的慢性影响是否依赖于TSC 2磷酸化和TSC对mTOR的抑制。我们发现，缺乏功能性TSC 2导致多种细胞类型中葡萄糖摄取和GLUT 1表达增加1.5至3倍。这些葡萄糖摄取和GLUT 1水平的增加通过用雷帕霉素抑制mTOR来防止。GSK-3抑制对TSC 2突变细胞的葡萄糖摄取或GLUT 1表达没有影响，表明GSK-3对GLUT 1和葡萄糖摄取的影响是由TSC 2/mTOR依赖性途径介导的。GSK-3抑制对GLUT 1表达和葡萄糖摄取的影响通过转染野生型TSC 2载体在TSC 2突变细胞中恢复，但不通过具有突变GSK-3磷酸化位点的TSC 2构建体恢复。因此，TSC 2和雷帕霉素敏感性mTOR在GSK-3的下游发挥作用，以调节GSK-3对葡萄糖摄取和GLUT 1表达的影响。因此，GSK-3通过TSC 2和mTOR抑制葡萄糖摄取，并可用于使能量底物利用与细胞生长相匹配。
Glucose transport is a highly regulated process and is dependent on a variety of signaling events. Glycogen synthase kinase-3 (GSK-3) has been implicated in various aspects of the regulation of glucose transport, but the mechanisms by which GSK-3 activity affects glucose uptake have not been well defined. We report that basal glycogen synthase kinase-3 (GSK-3) activity regulates glucose transport in several cell types. Chronic inhibition of basal GSK-3 activity (8-24 h) in several cell types, including vascular smooth muscle cells, resulted in an approximately twofold increase in glucose uptake due to a similar increase in protein expression of the facilitative glucose transporter 1 (GLUT1). Conversely, expression of a constitutively active form of GSK-3 beta resulted in at least a twofold decrease in GLUT1 expression and glucose uptake. Since GSK-3 can inhibit mammalian target of rapamycin (mTOR) signaling via phosphorylation of the tuberous sclerosis complex subunit 2 (TSC2) tumor suppressor, we investigated whether chronic GSK-3 effects on glucose uptake and GLUT1 expression depended on TSC2 phosphorylation and TSC inhibition of mTOR. We found that absence of functional TSC2 resulted in a 1.5- to 3-fold increase in glucose uptake and GLUT1 expression in multiple cell types. These increases in glucose uptake and GLUT1 levels were prevented by inhibition of mTOR with rapamycin. GSK-3 inhibition had no effect on glucose uptake or GLUT1 expression in TSC2 mutant cells, indicating that GSK-3 effects on GLUT1 and glucose uptake were mediated by a TSC2/mTOR-dependent pathway. The effect of GSK-3 inhibition on GLUT1 expression and glucose uptake was restored in TSC2 mutant cells by transfection of a wild-type TSC2 vector, but not by a TSC2 construct with mutated GSK-3 phosphorylation sites. Thus, TSC2 and rapamycin-sensitive mTOR function downstream of GSK-3 to modulate effects of GSK-3 on glucose uptake and GLUT1 expression. GSK-3 therefore suppresses glucose uptake via TSC2 and mTOR and may serve to match energy substrate utilization to cellular growth.