The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation

• Published in: Cell research Vol. 22; no. 8; pp. 1246 - 1257
• Main Authors: Guo, Hui-Ling, Zhang, Cixiong, Liu, Qi, Li, Qinxi, Lian, Guili, Wu, Di, Li, Xuebin, Zhang, Wei, Shen, Yuemao, Ye, Zhiyun, Lin, Shu-Yong, Lin, Sheng-Cai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2012; Nature Publishing Group
• Subjects: 2型糖尿病; 3T3-L1 Cells; 631/80/2023/2022; Adipocytes - drug effects; Adipocytes - metabolism; Animals; Axi; Axin Protein - genetics; Axin Protein - metabolism; Biomedical and Life Sciences; Blood; Blood Glucose - analysis; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Biology; Cell Membrane - genetics; Cell Membrane - metabolism; Enzyme Activation; Glucose; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; HEK293 Cells; Humans; Insulin; Insulin - administration & dosage; Insulin - pharmacology; Insulin Resistance; Kinesin - genetics; Kinesin - metabolism; Life Sciences; Male; Mice; Microscopy, Fluorescence; n蛋白; Original; original-article; Protein Interaction Mapping; Protein Stability; Protein Transport; RNA Interference; Signal Transduction; Tankyrases - genetics; Tankyrases - metabolism; trans-Golgi Network - metabolism; Translocation; Two-Hybrid System Techniques; 交互; 胰岛素; 蛋白复合物; 马达蛋白; 驱动蛋白; GLUT4 translocation; Axin; TNKS; KIF3A
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2012.52

Insulin-stimulated glucose uptake by the glucose transporter GLUT4 plays a central role in whole-body glucose homeostasis, dysregulation of which leads to type 2 diabetes. However, the molecular components and mechanisms regulating insulin-stimulated glucose uptake remain largely unclear. Here, we demonstrate that Axin interacts with the ADP-ribosylase tankyrase 2 （TNKS2） and the kinesin motor protein KIF3A, forming a ternary complex crucial for GLUT4 transiocation in response to insulin. Specific knockdown of the individual components of the complex attenuated insulin-stimulated GLUT4 translocation to the plasma membrane. Importantly, TNKS2-/- mice exhibit reduced insulin sensitivity and higher blood glucose levels when re-fed after fasting. Mechanistically, we demonstrate that in the absence of insulin, Axin, TNKS and KIF3A are co-localized with GLUT4 on the trans-Goigi network. Insulin treatment suppresses the ADP-ribosylase activity of TNKS, leading to a reduction in ADP ribosylation and ubiquitination of both Axin and TNKS, and a concurrent stabilization of the complex. Inhibition of Akt, the major effector kinase of insulin signaling, abrogates the insulin-mediated complex stabilization. We have thus elucidated a new protein complex that is directly associated with the motor protein kinesin in insulin-stimulated GLUT4 translo- cation.