title: Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B.
abstract: Recent data have implicated the serine/threonine protein kinase Akt/protein kinase B (PKB) in a diverse array of physiological pathways, raising the question of how biological specificity is maintained. Partial clarification derived from the observation that mice deficient in either of the two isoforms, Akt1/PKBalpha or Akt2/PKBbeta, demonstrate distinct abnormalities, i.e. reduced organismal size or insulin resistance, respectively. However, the question still persists as to whether these divergent phenotypes are due exclusively to tissue-specific differences in isoform expression or distinct capacities for signaling intrinsic to the two proteins. Here we show that Akt2/PKBbeta-/- adipocytes derived from immortalized mouse embryo fibroblasts display significantly reduced insulin-stimulated hexose uptake, clearly establishing that the partial defect in glucose disposal in these mice derives from lack of a cell autonomous function of Akt2/PKBbeta. Moreover, in adipocytes differentiated from primary fibroblasts or immortalized mouse embryo fibroblasts, and brown preadipocytes the absence of Akt2/PKBbeta resulted in reduction of insulin-induced hexose uptake and glucose transporter 4 (GLUT4) translocation, whereas Akt1/PKBalpha was dispensable for this effect. Most importantly, hexose uptake and GLUT4 translocation were completely restored after re-expression of Akt2/PKBbeta in Akt2/PKBbeta-/- adipocytes, but overexpression of Akt1/PKBalpha at comparable levels was ineffective at rescuing insulin action to normal. These results show that the Akt1/PKBalpha and Akt2/PKBbeta isoforms are uniquely adapted to preferentially transmit distinct biological signals, and this property is likely to contribute significantly to the ability of Akt/PKB to play a role in diverse processes.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.forename: Han
authors.initials: H
authors.lastname: Cho
authors.forename: James
authors.initials: J
authors.lastname: Mu
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
mesh_terms: D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006601:Hexoses / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006601:Hexoses; D007328:Insulin; D007527:Isoenzymes; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C495693:Slc2a4 protein, mouse; C494922:Akt2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose