The adaptor protein APPL2 inhibits insulin-stimulated glucose uptake by interacting with TBC1D1 in skeletal muscle

  1. Aimin Xu1,2,3
  1. 1State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong,
  2. 2Department of Medicine, The University of Hong Kong,
  3. 3Department of Pharmacology & Pharmacy, The University of Hong Kong,
  4. 4The Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences,
  5. 5Department of Biology, York University, Toronto, Canada.
  1. Corresponding Author: Aimin Xu or Kenneth KY Cheng, E-mail: amxu{at}, dorncky{at}


Insulin stimulates glucose uptake by promoting the trafficking of GLUT4 to the plasma membrane in muscle cells, and impairment of this insulin action contributes to hyperglycemia in type 2 diabetes. The adaptor protein APPL1 potentiates insulin-stimulated Akt activation and downstream actions. However, the physiological functions of APPL2, a close homologue of APPL1, in regulating glucose metabolism remain elusive. Here we showed that insulin-evoked plasma membrane recruitment of GLUT4 and glucose uptake were impaired by APPL2 overexpression, but enhanced by APPL2 knockdown. Likewise, conditional deletion of APPL2 in skeletal muscles enhanced insulin sensitivity, leading to an improvement of glucose tolerance. We identified the Rab-GTPase-activating protein TBC1D1 as an interacting partner of APPL2. Insulin stimulated TBC1D1 phosphorylation on serine-235, leading to enhanced interaction with the BAR domain of APPL2, which in turn suppressed insulin-evoked TBC1D1 phosphorylation on threonine-596 in cultured myotubes and skeletal muscle. Substitution of serine-235 with alanine diminished APPL2-mediated inhibition on insulin-dependent TBC1D1 phosphorylation on threonine-596 and the suppressive effects of TBC1D1 on insulin-induced glucose uptake and GLUT4 translocation to the plasma membrane in cultured myotubes. Therefore, the APPL2-TBC1D1 interaction serves as a key step to fine-tune insulin-stimulated glucose uptake by regulating the membrane recruitment of GLUT4 in skeletal muscle.


  • # KKY Cheng and W Zhu equally contribute in this study.

  • Received February 25, 2014.
  • Accepted May 23, 2014.

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