Flowchart: Preparation: Pkb

Text Box: Nfat





Text Box: PKB


Text Box: Mef2




Recent data have implicated the serine/threonine protein kinase Akt/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, using adipocytes differentiated from primary fibroblasts, immortalized mouse embryo fibroblasts, and brown preadipocytes, the absence of Akt2/PKBbeta resulted in reduction of insulin-induced hexose uptake and 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 to play a role in diverse processes