Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewStructure, regulation and function of PKB/AKT—a major therapeutic target
Introduction
Protein kinase Bα (PKBα) was initially identified by homology cloning [1]. The kinase domain is similar to that within protein kinase A (PKA) and protein kinase C (PKC), therefore it was termed Related to A and C-Protein Kinase (RAC-PK but later changed to PKB) [1], [2]. Soon after the product of a murine oncogene, v-Akt (AKT8 retrovirus), turned out to be a cellular homologue of PKB, termed c-Akt [3]. Two additional PKB family members have also been identified, PKBβ/c-Akt2 and PKBγ/c-Akt3 [4], [5]. The tissue distribution of PKB isoforms was recently determined using quantitative RT-PCR [6]. In mouse tissues, both the α and β isoforms are ubiquitously expressed, whereas the γ isoform is not detected in several tissues where α and β isoforms are highly expressed, but is relatively highly expressed in brain and testis. PKBβ is expressed predominantly in insulin target tissues, such as fat cells, liver and skeletal muscle. The PKB family of kinases is evolutionarily conserved in eukaryotes ranging from C. elegans to man (except yeast). The amino acid identity between C. elegans and human PKB is around 60%, whereas that between mouse, rat and human it is more than 95%. The three PKB isoforms share a similarity in their catalytic domain with a group of kinases from the AGC family that consists of more than 80 kinases. Most of these protein kinases are regulated by second messengers such as cyclic mononucleotides, Ca2+ or phosphoinositides and many of them are thought to be transducers of cell growth signalling (Fig. 1).
To date, most evidence suggests that PKB is a downstream target of several receptor tyrosine kinases that are regulated by physiological important cell stimuli, such as growth factors and insulin, and therefore plays a major role in metabolism, cell growth and cell survival. Identification of its downstream targets is an important task and will provide further evidence of the wide functional range of this kinase. Furthermore, several reports have described the contribution of PKB isoforms to human diseases, including cancer and diabetes (reviewed in [7], [8]), indicating that a precise understanding of the regulation and function of PKB would be of benefit to the management of these diseases. In this review, we describe molecular details of structure, regulation and function of PKB.
Section snippets
Domain structure of PKB
All three PKB isoforms consist of a conserved domain structure: an amino terminal pleckstrin homology (PH) domain, a central kinase domain and a carboxyl-terminal regulatory domain that contains the hydrophobic motif, a characteristic of AGC kinase (Fig. 1). The PH domain was originally found in pleckstrin, the major phosphorylation substrate for PKC in platelets [9]. The PH domain interacts with membrane lipid products such as phosphatidylinositol(3,4,5)trisphosphate [PtdIns(3,4,5)P3] produced
Upstream of PKB
Full activation of PKB is a multi-step process and several proteins responsible for each step have been identified and characterized [22] (Fig. 3). A number of stimuli can promote activation of PKB through the activation of receptor tyrosine kinases. One of the most significant findings in the early stages of PKB research was the PI3-kinase-dependent activation of PKB [23], [24], [25], [26]. PKB is activated by receptor tyrosine kinases such as platelet derived growth factor receptor (PDGF-R),
Physiological functions of PKB
PKB isoforms contribute to a variety of cellular responses, including cell growth, cell survival and metabolism. This multiplicity of PKB functions might be due to the variation and specificity of its substrates. Up to now, more than 50 proteins have been identified as putative substrates for PKB. Peptide sequences that are preferentially phosphorylated by PKB were characterized by Alessi et al. [74] and Obata et al. [75]. The minimal substrate consensus sequence for PKB, RXRXXS/T, where X is
Conclusions
The detailed knowledge of upstream regulators, and downstream targets, of PKB will be important to the understanding of normal cellular functions, as well as the management of human diseases such as cancer and diabetes. In the past 10 years, the mechanism for PKB activation, lipid second messenger-mediated phosphorylation of PKB, has been well characterized, except for the identification of the kinase(s) responsible for Ser473 phosphorylation. This is the missing piece of the puzzle in terms of
Acknowledgements
We thank David Barford (ICR, London) for preparing Fig. 3. Swiss Cancer League supports part of the work in the author's laboratory. The Friedrich Miescher Institute is part of the Novartis Research Foundation.
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