Akt signalling in health and disease

被引:1095
作者
Hers, Ingeborg [2 ]
Vincent, Emma E. [1 ]
Tavare, Jeremy M. [1 ]
机构
[1] Univ Bristol, Sch Biochem, Bristol BS8 1TD, Avon, England
[2] Univ Bristol, Sch Physiol & Pharmacol, Bristol BS8 1TD, Avon, England
基金
英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
Akt; Protein kinase B; PI3; kinase; Diabetes; Cancer; Cardiovascular disease; PROTEIN-KINASE-B; PLECKSTRIN-HOMOLOGY-DOMAIN; CELL LUNG-CANCER; INSULIN-RECEPTOR SUBSTRATE-1; GLYCOGEN-SYNTHASE KINASE-3; NITRIC-OXIDE SYNTHASE; SERINE-THREONINE KINASE; GROWTH-FACTOR RECEPTOR; SKELETAL-MUSCLE CELLS; NF-KAPPA-B;
D O I
10.1016/j.cellsig.2011.05.004
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKB alpha/beta/gamma respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt: this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:1515 / 1527
页数:13
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