ReviewAkt signalling in health and disease☆
Introduction
Akt (also known as protein kinase B or PKB) was originally identified by Stephen Staal in 1987 as the likely transforming gene component, v-Akt, of the Akt8 provirus [1]. In this same study Staal identified the human homologue of v-Akt, Akt1, which was amplified twenty-fold in a gastric adenocarcinoma. Eight years later in 1995 Richard Roth and his colleagues reported that Akt was activated by insulin [2]. This immediately led to a huge surge in interest in the regulation and role of this protein kinase. We now know that the Akt family comprises three closely and evolutionary related isoforms (Akt1/2/3 or PKBα/β/γ) which have a highly conserved domain structure; an N-terminal pleckstrin homology (PH) domain, a kinase domain and a C-terminal regulatory tail containing a hydrophobic motif [3]. We also have a very advanced, albeit still incomplete, understanding of how Akt isoforms are activated and the mechanisms by which these enzymes bring about some of their diverse array of biological effects on cells and tissues.
In this review we will briefly discuss our current understanding of how Akt isoforms are regulated and the substrate proteins they phosphorylate. We will then integrate this information with a view of the role of Akt in four disease states; cancer, diabetes, cardiovascular disease and neurological disorders. The biopharmaceutical industry has invested substantially in developing inhibitors of Akt isoforms for the treatment of various cancers. While the jury is still out on whether this approach will improve or extend lives of patients with cancer, we discuss the types of inhibitors that have been developed and the potential on- and off-target toxicities that such drugs may exhibit during clinical trials.
Section snippets
Regulation of Akt
Akt1 has a wide tissue distribution and is implicated in cell growth and survival [4], [5], whereas Akt2 is highly expressed in muscle and adipocytes and contributes to insulin-mediated regulation of glucose homeostasis [6], [7]. The distribution of Akt3 is more restricted with expression mainly found in the testes and brain [8].
Akt is one of the key molecules activated downstream of the PI3 kinase signalling pathway. Many growth factors and cytokines stimulate an increase in activity in the
Akt effectors
Akt regulates many cellular processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (see Fig. 2). Some of these substrates carry out more than one function and one process is often mediated by several downstream targets. Identification of substrates has been greatly aided by the definition of a minimal recognition sequence for Akt, RXRXX(pS/pT)Ψ, where R denotes
Role of Akt signalling in disease
As a consequence of the central importance of Akt in such a wide range of cellular processors, including metabolism, proliferation and survival, dysregulation of the kinase is associated with several human diseases including cancer, diabetes, cardiovascular and neurological diseases. The role of dysregulated Akt signalling in these disease states is discussed in the sections below.
Akt as a drug target
There have been intense efforts to identify cell permeant Akt inhibitors, given its central role in tumourigenesis. Several sites on the protein provide functionally important regions that are suitable for binding small molecule inhibitors. This includes the ATP binding pocket that has been so successfully targeted in other protein kinases [199], the phosphoinositide binding pocket of the PH domain, a hinge region lying between the PH and protein kinase domains, and the substrate binding groove
Conclusions/summary
Our understanding of the mechanism by which Akt is activated is now relatively well understood, although there are still gaps in our knowledge of the basis by which mTORC2-directed phosphorylation of Ser473 is controlled. There are numerous substrates for Akt which have been identified and many of these can be ascribed a role in the diverse array of downstream biological effects of Akt signalling on cells and provide an explanation for the role of Akt in cancer, diabetes, cardiovascular disease
Acknowledgements
The authors are grateful to Dr Roger W. Hunter for his help in creating the figures and the following organisations for funding our own work that has been cited in this review: The Medical Research Council, Wellcome Trust, British Heart Foundation, DiabetesUK and the Biotechnology and Biological Sciences Research Council.
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All authors contributed equally to this review.