Elsevier

Cellular Signalling

Volume 23, Issue 10, October 2011, Pages 1515-1527
Cellular Signalling

Review
Akt signalling in health and disease

https://doi.org/10.1016/j.cellsig.2011.05.004Get rights and content

Abstract

Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ 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.

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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