Associate editor: D. ShugarInhibition of protein kinase B/Akt: implications for cancer therapy
Introduction
Protein kinase B (PKBα, also called Akt-1) was cloned in 1991 by three independent groups, based on its homology to protein kinases A (PKA) and C (PKC) Coffer & Woodgett, 1991, Jones et al., 1991b or as the cellular homolog to the retroviral oncogene viral akt (v-Akt) (Bellacosa et al., 1991). In humans, three PKB genes have been identified, termed Akt1/PKBα, Akt2/PKBβ Jones et al., 1991a, Cheng et al., 1992, and Akt3/PKBγ (Brodbeck et al., 1999). In addition, two C-terminal splice variants have been reported: PKBβ1 contains a 40-amino acid C-terminal extension (Jones et al., 1991a), while PKBγ1 has a unique C-terminus (Brodbeck et al., 2001). Based on its kinase domain sequences, PKB is a member of the AGC group of kinases, which includes many kinases that are regulated by second messengers, such as PKA diacylglycerol-activated and phospholipid-dependent PKC. PKB is activated downstream of phosphoinositide 3-kinase (PI-3K), requiring the membrane-bound second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) Cross et al., 1995, Franke et al., 1995, Burgering & Coffer, 1995.
Section snippets
Regulation of protein kinase B activity
Structurally, all PKB isoforms are composed of an N-terminal pleckstrin homology (PH) domain, a central kinase catalytic domain, and a C-terminal hydrophobic regulatory domain (Fig. 1). Activation of PKBα by growth factors involves a PI-3K- and PH domain-dependent membrane translocation step, followed by phosphorylation of two key regulatory sites, Thr308 in the activation loop in the kinase domain and Ser473 in the C-terminal regulatory domain (Fig. 2) (Alessi et al., 1996a). With the
Role for protein kinase B in cancer
Akt1/PKBα originally was reported as the cellular counterpart of the viral oncogene, which was amplified in a gastric adenocarcinoma (Staal, 1987). Over-expression of PKB isoforms has now been reported in ovarian, breast, prostrate, and pancreatic cancers Cheng et al., 1992, Cheng et al., 1996, Bellacosa et al., 1995, Nakatani et al., 1999. In addition, PKB activity is increased in cancers where the tumor suppressor PTEN is mutated (see Yamada & Araki, 2001). As mentioned in Section 2.4, PTEN
Role of protein kinase B in diabetes
Initial reports on PKB signaling suggested a role for this kinase in insulin regulation of glucose metabolism Cross et al., 1995, Kohn et al., 1996. While some contradictory data have been reported, there is strong evidence for the involvement of PKB in insulin-stimulated glucose uptake into muscle and adipocytes, and an impairment of PKB function in insulin resistance and diabetes (see Hajduch et al., 2001). Perhaps the strongest evidence comes from studies in mice with targeted disruption of
Inhibition of protein kinase B signaling
As described in Section 3, uncontrolled activation of PKB, either due to gene amplification or mutation/loss of PTEN, leads to the development of cancer. Inhibition of PKB activity is, thus, an attractive strategy for cancer therapy. While a specific PKB inhibitor has not been reported yet, the potential therapeutic values of such an inhibitor can be gathered from some recent studies.
Conclusions and perspectives
Research in the last 10 years has established PKB as an important regulator of cell growth, proliferation, and metabolism (see Brazil & Hemmings, 2001). As PKB promotes both cell survival and proliferation, specific inhibition of its activity is a good therapeutic strategy for tumors with amplification of PKB or mutation in PTEN. The recent success of STI571 (Glivec), a specific inhibitor of Abl tyrosine kinase, in the treatment of chronic myeloid leukemia shows the efficacy of molecularly
Acknowledgements
Friedrich Miescher Institute is funded by the Novartis Research Foundation. Work in the authors’ laboratory is funded partly by the Swiss Cancer League. We thank I. Galetic for comments on the manuscript and S-M. Maira for preparation of Fig. 2.
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