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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.

SUBMITTER: Guo HL 

PROVIDER: S-EPMC3411167 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Guo Hui-Ling HL   Zhang Cixiong C   Liu Qi Q   Li Qinxi Q   Lian Guili G   Wu Di D   Li Xuebin X   Zhang Wei W   Shen Yuemao Y   Ye Zhiyun Z   Lin Shu-Yong SY   Lin Sheng-Cai SC  

Cell research 20120403 8


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. Specif  ...[more]

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