The Akt kinases Isoform specificity in metabolism and cancer英文文献.pdfVIP

[Cell Cycle 8:16, 2502-2508; 15 August 2009]; ©2009 Landes Bioscience Extra View The Akt kinases Isoform specificity in metabolism and cancer Eva Gonzalez and Timothy E. McGraw* Department of Biochemistry; Weill Cornell Medical College; New York, NY USA Key words: Akt, isoforms, metabolism, cancer, glucose homeostasis, GLUT4, signaling specificity, cellular growth, Akt1, Akt2 The Akt (PKB) protein kinases are critical regulators of human Akt is phosphorylated at two sites, one within the T-loop of the physiology that control an impressive array of diverse cellular catalytic domain (Thr308, Akt1 residue) by the phosphoinositide- functions, including the modulation of growth, survival, prolif- dependent kinase 1 (PDK1) and within the carboxyl terminal eration and metabolism. The Akt kinase family is comprised of hydrophobic domain (Ser473, Akt1 residue) by the mammalian three highly homologous isoforms: Akt1 (PKBα), Akt2 (PKBβ) target of rapamycin complex 2 (mTORC2).3,4 Targeting of Akt and Akt3 (PKBγ). Phenotypic analyses of Akt isoform knockout to the plasma membrane, independent of external stimuli (or PI3 mice documented Akt isoform specific functions in the regulation kinase activity), results in Akt activation, strongly suggesting that of cellular growth, glucose homeostasis and neuronal develop- activation is limited predominantly by recruitment to the plasma ment. Those studies establish that the functions of the different membrane rather than the direct modulation of PDK1 and/or Akt kinases are not completely overlapping and that isoform- mTORC2 activities. Akt is transiently localized to the plasma specific signaling contributes to