Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
Author for correspondence (e-mail: brian.hemmings{at}fmi.ch)
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Introduction |
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PKB regulation |
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The serine/threonine kinase phosphoinositide-dependent kinase 1 (PDK1), once recruited to the plasma membrane by PtdIns(3,4,5)P3 through its PH domain, is the kinase responsible for the phosphorylation of Thr308 (Alessi et al., 1997; Stephens et al., 1998
). However, the identity of the Ser473 kinase (S473K, also called PDK2) is still controversial. Several candidates have been proposed, including PKB itself (Toker and Newton, 2000
), PDK1 (Balendran et al., 1999
), integrin-linked kinase 1 (ILK1) (Persad et al., 2001
), mitogen activated protein kinase activated protein kinase 2 (MAPKAP-K2) (Alessi et al., 1996
), protein kinase C ßII (PKCßII) (Kawakami et al., 2004
), and the members of the atypical PI 3-kinase related protein kinase (PIKK) family: DNA-dependent protein kinase (DNA-PK) (Feng et al., 2004
), ataxia telangiectasia mutant (ATM) (Viniegra et al., 2005
) and, more recently, the rapamycin-insensitive mTOR complex TORC2 (Sarbassov et al., 2005
). While their relative physiological significance remains to be determined, S473K activity is probably partially redundant and the identity of the kinase might depend on the cellular and physiological context. Phosphorylation of Ser473 is the key step in the activation of PKB because it stabilizes the active conformation state (Yang et al., 2002
). Once activated at the plasma membrane, phosphorylated PKB can translocate to the cytosol or the nucleus (Andjelkovic et al., 1999
).
Interestingly, a number of PKB-binding proteins have been shown to modulate PKB activity further in either a positive or negative manner. This suggests transient regulation of the kinase by adaptator proteins (Brazil et al., 2002; Song et al., 2005
). Moreover, several phosphatases negatively regulate PKB activity. The tumor suppressor phosphatase and tensin homology deleted on chromosome ten (PTEN) (Stambolic et al., 1998
) and the SH2-domain-containing inositol polyphosphate 5-phosphatase (SHIP) (Huber et al., 1999
) inhibit PKB activity indirectly by converting PtdIns(3,4,5)P3 to PtdIns(4,5)P2 and PtdIns(3,4)P2. Protein phosphatase 2A (PP2A) and PH domain leucine-rich repeat protein phosphatase (PHLPP
) do so directly by dephosphorylating Ser473 and/or Thr308 on PKB (Andjelkovic et al., 1996
; Gao et al., 2005
). Although PKB is also proposed to be activated in a PI 3-kinase-independent manner (Vanhaesebroeck and Alessi, 2000
), the physiological significance of these findings requires further study.
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PKB in physiology |
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Genetic manipulation of Pkb genes in mice, either by transgenic or knockout approaches, has brought novel insights into PKB signalling (Brazil et al., 2004; Yang et al., 2004
and references therein). These studies identified a wide range of in vivo functions of PKB, revealing tissue-specific requirements for the different PKB isoforms in metabolism and embryonic development. Various transgenic mice expressing constitutively active PKB under the control of tissue-specific promoters have been generated. From the analysis of these, it appears that PKB plays a major role in cell growth: overexpression of active PKB leads to cardiac or skeletal muscle hypertrophy and an increase in ß-cell mass and size, as well as potentially promoting the progression of tumours such as T cell lymphoma or prostate intraepithelial neoplasia (Lai et al., 2004
; Yang et al., 2004
). Interestingly, recent results from transgenic mice expressing a kinase-dead mutant of PKB
in ß cells suggest that it is also involved in the regulation of the insulin secretory pathway (Bernal-Mizrachi et al., 2004
). Expression of activated PKB
in the mammary gland results in delayed involution and the induction of lipid synthesis, leading to an increase in milk fat content and lactation defects (Schwertfeger et al., 2001
; Schwertfeger et al., 2003
). Finally, PKB has been shown to exert a neuroprotective effect against ischemic brain damage in genetically modified mice expressing an active form of PKB in neuronal cells (Ohba et al., 2004
).
The Pkb/Akt1, Pkbß/Akt2 or Pkb
/Akt3 genes in mice have been targeted by homologous recombination. Pkb
/Akt1 deficiency results in significant neonatal mortality (Cho et al., 2001
; Yang et al., 2003
) and growth retardation due to a defect in placental development (Chen et al., 2001
; Cho et al., 2001
; Yang et al., 2003
). By contrast, Pkbß/Akt2/ mice display insulin resistance and a type-II-diabetes-like syndrome. Furthermore, the absence of Pkbß/Akt2 is accompanied by mild growth-retardation and age-dependent loss of adipose tissue. Both Pkb
/Akt1 and Pkbß/Akt2 are required for normal platelet aggregation (Chen et al., 2004
; Woulfe et al., 2004
).
Recently, PKB has been shown to play an essential role in postnatal brain development; Pkb
/Akt3/ mice are characterized by a 20-25% reduction in brain size and weight, which is partially due to a decrease in cell size and cell number (Easton et al., 2005
; Tschopp et al., 2005
). Simultaneous inactivation of two PKB isoforms in mice leads to a more severe phenotype: for instance, Pkb
/Akt1-Pkbß/Akt2 double-knockout mutants die immediately after birth and exhibit dwarfism, impairment of adipogenesis and defects in skin, skeletal muscle and bone development (Peng et al., 2003
). Overall, the phenotypic analysis of these mouse models highlights the specific functions of each PKB isoform in vivo and the necessity for cells to preserve a crucial level of PKB activity for normal growth, metabolism and differentiation. Additional combinations of Pkb/Akt knockout mice should provide further insights in the physiological role of PKB.
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PKB deregulation and human diseases |
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PKB is an attractive therapeutic target for treatment of cancer, and novel PH-domain-dependent inhibitors have recently been reported to exhibit PKB specificity (Barnett et al., 2005). However, only a subset of the cellular processes regulated by the PI-3-kinasePKB pathway are involved in cancer progression. Therefore, the choice of drug targets should also take into account the adverse effects that could result from the inhibition of other PKB-regulated cellular processes, such as glucose metabolism, in which inhibition of PKB potentially leads to a diabetes-like syndrome (Luo et al., 2005
). Furthermore, it is also crucial to keep in mind the potentially opposing effects of different PKB isoforms in cancer progression. Whereas a reduction in metastasis is observed upon Pkb
/Akt1 expression owing to increased differentiation (Hutchinson et al., 2004
) overexpression of Pkbß/Akt2 has been associated with invasion and metastasis (Arboleda et al., 2003
). Therefore, pharmaceutical inhibitors specific for each PKB isoform will be crucial for treatment of diseases that exhibit abnormal PKB signalling.
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Acknowledgments |
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Footnotes |
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References |
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