title: Tropomodulin3 is a novel Akt2 effector regulating insulin-stimulated GLUT4 exocytosis through cortical actin remodeling.
abstract: Akt2 and its downstream effectors mediate insulin-stimulated GLUT4-storage vesicle (GSV) translocation and fusion with the plasma membrane (PM). Using mass spectrometry, we identify actin-capping protein Tropomodulin 3 (Tmod3) as an Akt2-interacting partner in 3T3-L1 adipocytes. We demonstrate that Tmod3 is phosphorylated at Ser71 on insulin-stimulated Akt2 activation, and Ser71 phosphorylation is required for insulin-stimulated GLUT4 PM insertion and glucose uptake. Phosphorylated Tmod3 regulates insulin-induced actin remodelling, an essential step for GSV fusion with the PM. Furthermore, the interaction of Tmod3 with its cognate tropomyosin partner, Tm5NM1 is necessary for GSV exocytosis and glucose uptake. Together these results establish Tmod3 as a novel Akt2 effector that mediates insulin-induced cortical actin remodelling and subsequent GLUT4 membrane insertion. Our findings suggest that defects in cytoskeletal remodelling may contribute to impaired GLUT4 exocytosis and glucose uptake.
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Singapore.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Lim
authors.affiliation: 1] Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Singapore [2] Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Bi
authors.affiliation: The Key Laboratory of Regenerative Biology and The Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.affiliation: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Oncology Research Unit, School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gunning
authors.affiliation: The Key Laboratory of Regenerative Biology and The Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Singapore.
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D041721:3T3-L1 Cells; D000199:Actins / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051348:Tropomodulin / Q000378:metabolism*
chemical_list: D000199:Actins; D051275:Glucose Transporter Type 4; D007328:Insulin; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C495836:TMOD3 protein, human; C495837:Tmod3 protein, mouse; D051348:Tropomodulin; C494921:AKT2 protein, human; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose