title: Focal Adhesion Kinase contributes to insulin-induced actin reorganization into a mesh harboring Glucose transporter-4 in insulin resistant skeletal muscle cells.
abstract: BACKGROUND
  Focal Adhesion Kinase (FAK) is recently reported to regulate insulin resistance by regulating glucose uptake in C2C12 skeletal muscle cells. However, the underlying mechanism for FAK-mediated glucose transporter-4 translocation (Glut-4), responsible for glucose uptake, remains unknown. Recently actin remodeling was reported to be essential for Glut-4 translocation. Therefore, we investigated whether FAK contributes to insulin-induced actin remodeling and harbor Glut-4 for glucose transport and whether downregulation of FAK affects the remodeling and causes insulin resistance.
  
  
  RESULTS
  To address the issue we employed two approaches: gain of function by overexpressing FAK and loss of function by siRNA-mediated silencing of FAK. We observed that overexpression of FAK induces actin remodeling in skeletal muscle cells in presence of insulin. Concomitant to this Glut-4 molecules were also observed to be present in the vicinity of remodeled actin, as indicated by the colocalization studies. FAK-mediated actin remodeling resulted into subsequent glucose uptake via PI3K-dependent pathway. On the other hand FAK silencing reduced actin remodeling affecting Glut-4 translocation resulting into insulin resistance.
  
  
  CONCLUSIONS
  The data confirms that FAK regulates glucose uptake through actin reorganization in skeletal muscle. FAK overexpression supports actin remodeling and subsequent glucose uptake in a PI3K dependent manner. Inhibition of FAK prevents insulin-stimulated remodeling of actin filaments resulting into decreased Glut-4 translocation and glucose uptake generating insulin resistance. To our knowledge this is the first study relating FAK, actin remodeling, Glut-4 translocation and glucose uptake and their interrelationship in generating insulin resistance.
authors.affiliation: Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, Punjab, 160 062, India. csdey@niper.ac.in
authors.forename: Bharti
authors.initials: B
authors.lastname: Bisht
authors.forename: Chinmoy S
authors.initials: CS
authors.lastname: Dey
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection
chemical_list: D000199:Actins; D051275:Glucose Transporter Type 4; D007328:Insulin; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005947:Glucose
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