title: Regulatory mode shift of Tbc1d1 is required for acquisition of insulin-responsive GLUT4-trafficking activity.
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 insulin-responsiveness 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.
authors: Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi, Japan.
authors: Hiroyasu
authors: H
authors: Hatakeyama
authors: Makoto
authors: M
authors: Kanzaki
mesh_terms: D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D051379:Mice; D009132:Muscles / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D005082:Physical Exertion; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C528734:GLUT4 enhancer factor, mouse; D020690:GTPase-Activating Proteins; D007328:Insulin; D009687:Nuclear Proteins; D012265:Ribonucleotides; C095906:Tbc1d1 protein, mouse; C505647:Tbc1d4 protein, mouse; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide