Regulatory mode shift of Tbc1d1 is required for acquisition of insulin-responsive GLUT4-trafficking activity

Hiroyasu Hatakeyama, Makoto Kanzaki

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Tbc1d1 is key to skeletal muscle GLUT4 regulation. By using GLUT4 nanometry combined with a cell-based reconstitution model, we uncover a shift in the regulatory mode of Tbc1d1 by showing that Tbc1d1 temporally acquires insulin responsiveness, which triggers GLUT4 trafficking only after an exercise-mimetic stimulus such as aminoimidazole carboxamide ribonucleotide (AICAR) pretreatment. The functional acquisition of insulin responsiveness requires Ser-237 phosphorylation and an intact phosphotyrosine-binding (PTB) 1 domain. Mutations in PTB1, including R125W (a natural mutant), thus result in complete loss of insulinresponsiveness acquisition, whereas AICAR-responsive GLUT4-liberation activity remains intact. Thus our data provide novel insights into temporal acquisition/memorization of Tbc1d1 insulin responsiveness, relying on the PTB1 domain, possibly a key factor in the beneficial effects of exercise on muscle insulin potency.

Original languageEnglish
Pages (from-to)809-817
Number of pages9
JournalMolecular biology of the cell
Volume24
Issue number6
DOIs
Publication statusPublished - 2013 Mar 15

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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