title: The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation.
abstract: 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 translocation 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-Golgi 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 translocation.
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Guo
authors.forename: Cixiong
authors.initials: C
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.forename: Guili
authors.initials: G
authors.lastname: Lian
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Xuebin
authors.initials: X
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.forename: Shu-Yong
authors.initials: SY
authors.lastname: Lin
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D025941:Protein Interaction Mapping; D055550:Protein Stability; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction; D038501:Tankyrases / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D060466:Axin Protein; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; C490202:Kif3a protein, mouse; C495693:Slc2a4 protein, mouse; D038501:Tankyrases; C511054:tankyrase-2, mouse; D016547:Kinesins