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Cell Death and Differentiation

Cell Death and Differentiation

IF: 15.4
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AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake.

Published:27 May 2021 DOI: PMID: 34045668
Xi Sheng Rao, Xiao Xia Cong, Xiu Kui Gao, Yin Pu Shi, Lin Jing Shi, Jian Feng Wang, Chen-Yao Ni, Ming Jie He, Yingke Xu, Cong Yi, Zhuo-Xian Meng, Jinling Liu, Peng Lin, Li Ling Zheng, Yi Ting Zhou

Abstract

Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1–306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
AICAR 2627-69-2 C9H14N4O5 401 suppliers $25.00-$15640.00
AICAR 2627-69-2 C9H14N4O5 401 suppliers $25.00-$15640.00
AICAR 2627-69-2 C9H14N4O5 401 suppliers $25.00-$15640.00
AICAR 2627-69-2 C9H14N4O5 401 suppliers $25.00-$15640.00
6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE 866405-64-3 C24H25N5O 269 suppliers $8.00-$2492.00
6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE 866405-64-3 C24H25N5O 269 suppliers $8.00-$2492.00
6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE 866405-64-3 C24H25N5O 269 suppliers $8.00-$2492.00
6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE 866405-64-3 C24H25N5O 269 suppliers $8.00-$2492.00

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