title: Signaling specificity in the Akt pathway in biology and disease.
abstract: Akt/PKB is a key master regulator of a wide range of physiological functions including metabolism, proliferation, survival, growth, angiogenesis and migration and invasion. The Akt protein kinase family comprises three highly related isoforms encoded by different genes. The initial observation that the Akt isoforms share upstream activators as well as several downstream effectors, together with the high sequence homology suggested that their functions were mostly redundant. By contrast, an increasing body of evidence has recently uncovered the concept of Akt isoform signaling specificity, supported by distinct phenotypes displayed by animal strains genetically modified for each of the three genes, as well as by the identification of isoform-specific substrates and association with discrete subcellular locations. Given that Akt is regarded as a promising therapeutic target in a number of pathologies, it is essential to dissect the relative contributions of each isoform, as well as the degree of compensation in pathophysiological function. Here we summarize our view of how Akt selectivity is achieved in the context of subcellular localization, isoform-specific substrate phosphorylation and context-dependent functions in normal and pathophysiological settings.
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: atoker@bidmc.harvard.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Italy. Electronic address: sandra.marmiroli@unimore.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Marmiroli
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D020033:Protein Isoforms; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2
keywords: Akt; Cancer; Nucleus; PI 3-Kinase; Protein kinase; Signaling