AKT1

AKT1 Background

AKT1, encoded by the Akt1 gene, is the predominantly expressed isoform of the AKT family. AKT was named after a cell transforming retrovirus found in a spontaneous thymic lymphoma of an AKR mouse ^[1]. It is also called RAC-alpha serine/threonine-protein kinase, v-akt murine thymoma viral oncogene homolog, or protein kinase B (PKB). AKT1 mainly localizes at the plasma membrane and cytosol, and it may translocate to the nucleus after growth factor stimulation ^[2][3]. AKT1 is activated by phosphorylation at two regulatory sites Thr308 and Ser473 through various factors such as insulin, PI3K (phosphatidylinositol 3-kinase), and IGF1 (insulin-like growth factor 1) ^[4][5]. Activated AKT1 phosphorylates serine or threonine residues on a range of downstream substrates regulating cell growth, metabolism, apoptosis, angiogenesis, and drug responses. AKT1 kinase helps control apoptosis, which is the self-destruction of cells when they become damaged or are no longer needed. Due to its involvement in various cellular processes that promote cell survival and growth, the AKT pathway is a major target for cancer drug discovery. The PI3K/AKT/mammalian target of the rapamycin (mTOR) signaling pathway is hyperactivated or altered in many cancers and regulates a broad range of cellular processes including survival, proliferation, growth, metabolism, angiogenesis, and metastasis ^[6]. The RAF/MEK/ERK pathway is a main compensatory pathway in the downstream events of the PI3K/AKT/mTOR pathway ^[7]. Furthermore, activation of AKT and Ras pathways is often implicated in carcinogenesis ^[7]. AKT1 also stimulates glucose uptake by mediating insulin-induced translocation of Glut-4 (glucose transporter 4) to the plasma membrane of fat and muscle cells ^[8]. Post-mortem brain studies of schizophrenic patients have identified a reduced level of AKT1 in the frontal cortex ^[9]. Besides, the AKT1 signaling pathway also mediates FOXO1-dependent autophagy induced by FOXO3 ^[10].

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[3] Meier R., Alessi D. R., et al. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta [J]. J. Biol. Chem. 1997, 272, 30491-30497.
[4] Alessi DR, Andjelkovic M, et al. Mechanism of activation of protein kinase B by insulin and IGF-1 [J]. EMBO J. 1996; 15:6541–6551.
[5] Kitamura T, Ogawa W, et al. Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport [J]. Mol Cell Biol. 1998;18:3708-3717.
[6] Ersahin T, Tuncbag N, et al. The PI3K/AKT/mTOR interactive pathway [J]. Mol Biosyst. 2015 Jul;11(7):1946-54.
[7] Ho C1, Wang C, et al. AKT (v-akt murine thymoma viral oncogene homolog 1) and N-Ras (neuroblastoma ras viral oncogene homolog) coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR (mammalian target of rapamycin complex 1), FOXM1 (forkhead box M1)/SKP2, and c-Myc pathways [J]. Hepatology. 2012 Mar;55(3):833-45.
[8] Kohn AD, Summers SA, et al. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation [J]. J Biol Chem. 1996; 271:31372-31378.
[9] Cohen MM Jr. The AKT genes and their roles in various disorders [J]. Am J Med Genet A. 2013 Dec;161A(12):2931-7.
[10] Jingyi Zhou, Wenjuan Liao, et al. FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway [J]. Autophagy vol. 8,12 (2012): 1712-23.