GSK3α phosphorylates dynamin-2 to promote GLUT4 endocytosis in muscle cells.

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  • Additional Information
    • Source:
      Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 0375356 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1540-8140 (Electronic) Linking ISSN: 00219525 NLM ISO Abbreviation: J Cell Biol Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York : Rockefeller University Press
    • Subject Terms:
      Dynamin II*/metabolism ; Endocytosis* ; Glucose Transporter Type 4*/metabolism ; Glycogen Synthase Kinase 3*/metabolism ; Muscle Cells*/metabolism; Animals ; Mice ; Adaptor Proteins, Signal Transducing ; Glucose ; Insulin ; Insulin Resistance
    • Abstract:
      Insulin-stimulated translocation of glucose transporter 4 (GLUT4) to plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2) in catalyzing GLUT4 endocytosis is negatively regulated by insulin signaling in muscle cells. Mechanistically, the fission activity of Dyn2 is inhibited by binding with the SH3 domain of Bin1. In the absence of insulin, GSK3α phosphorylates Dyn2 to relieve the inhibition of Bin1 and promotes endocytosis. Conversely, insulin signaling inactivates GSK3α and leads to attenuated GLUT4 internalization. Furthermore, the isoform-specific pharmacological inhibition of GSK3α significantly improves insulin sensitivity and glucose tolerance in diet-induced insulin-resistant mice. Together, we identify a new role of GSK3α in insulin-stimulated glucose disposal by regulating Dyn2-mediated GLUT4 endocytosis in muscle cells. These results highlight the isoform-specific function of GSK3α on membrane trafficking and its potential as a therapeutic target for metabolic disorders.
      (© 2022 Laiman et al.)
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    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Bin1 protein, mouse)
      EC 3.6.5.5 (Dynamin II)
      IY9XDZ35W2 (Glucose)
      0 (Glucose Transporter Type 4)
      EC 2.7.11.26 (Glycogen Synthase Kinase 3)
      0 (Insulin)
      0 (Slc2a4 protein, mouse)
      EC 3.6.5.5 (DNM2 protein, mouse)
    • Publication Date:
      Date Created: 20221129 Date Completed: 20221202 Latest Revision: 20230228
    • Publication Date:
      20231215
    • Accession Number:
      PMC9712776
    • Accession Number:
      10.1083/jcb.202102119
    • Accession Number:
      36445308