Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation
Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation
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DOI：
10.1074/jbc.m708934200
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发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Lienhard, Gustav E.
中科院分区：
文献类型：
--
作者：
Chavez, Jose A.;Roach, William G.;Lienhard, Gustav E.
胰岛素通过刺激细胞内GLUT 4向细胞表面的运输来增加葡萄糖转运，该过程称为GLUT 4易位。AS 160是一种Rab GTP酶激活蛋白（GAP），其活性似乎受到Akt磷酸化的抑制。Tbc 1d 1是一个Rab GAP，其序列与AS 160高度相似，并且具有与AS 160相同的Rab特异性。Tbc 1d 1在调节GLUT 4运输中的作用尚不清楚。我们以前的研究表明，过表达的Tbc 1d 1抑制胰岛素刺激的GLUT 4易位在3 T3-L1脂肪细胞，即使胰岛素引起磷酸化的单一经典Akt基序。在本研究中，我们发现在3 T3-L1脂肪细胞中，Tbc 1d 1的丰度仅为AS 160的1/20，Tbc 1d 1的敲低对胰岛素刺激的GLUT 4易位没有影响，并且过表达的Tbc 1d 1也抑制由激活的Akt表达引起的GLUT 4易位。这些结果表明，内源性Tbc 1d 1不参与胰岛素调节的GLUT 4在脂肪细胞中的易位，并表明Tbc 1d 1差距活性不受Akt磷酸化的抑制。此外，我们发现Tbc 1d 1在骨骼肌中的表达比在脂肪中高得多，并且AMP激活的蛋白激酶（AMPK）激活剂5 '-氨基咪唑-4-甲酰胺核糖核苷部分逆转了3 T3-L1脂肪细胞中过表达的Tbc 1d 1对胰岛素刺激的GLUT 4易位的抑制。已知激酶AMPK的5 '-氨基咪唑-4-甲酰胺核糖核苷活化引起肌肉中的GLUT 4易位。上述结果强烈表明，Tbc 1d 1是导致肌肉中AMPK刺激的GLUT 4易位的信号转导途径中的一个组分。
Insulin increases glucose transport by stimulating the trafficking of intracellular GLUT4 to the cell surface, a process known as GLUT4 translocation. A key protein in signaling this process is AS160, a Rab GTPase-activating protein ( GAP) whose activity appears to be suppressed by Akt phosphorylation. Tbc1d1 is a Rab GAP with a sequence highly similar to that of AS160 and with the same Rab specificity as that of AS160. The role of Tbc1d1 in regulating GLUT4 trafficking has been unclear. Our previous study showed that overexpressed Tbc1d1 inhibited insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes, even though insulin caused phosphorylation on its single canonical Akt motif. In the present study, we show in 3T3-L1 adipocytes that Tbc1d1 is only 1/20 as abundant as AS160, that knockdown of Tbc1d1 has no effect on insulin-stimulated GLUT4 translocation, and that overexpressed Tbc1d1 also inhibits GLUT4 translocation elicited by activated Akt expression. These results indicate that endogenous Tbc1d1 does not participate in insulin-regulated GLUT4 translocation in adipocytes and suggest that the GAP activity of Tbc1d1 is not suppressed by Akt phosphorylation. In addition, we discovered that Tbc1d1 is much more highly expressed in skeletal muscle than fat and that the AMP-activated protein kinase ( AMPK) activator 5'-aminoimidazole-4-carboxamide ribonucleoside partially reversed the inhibition of insulin-stimulated GLUT4 translocation by overexpressed Tbc1d1 in 3T3-L1 adipocytes. 5'-Aminoimidazole-4-carboxamide ribonucleoside activation of the kinase AMPK is known to cause GLUT4 translocation in muscle. The above findings strongly suggest that Tbc1d1 is a component in the signal transduction pathway leading to AMPK-stimulated GLUT4 translocation in muscle.