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Cell Science at a Glance 5675

Protein B/Akt at progression. Conserved from primitive This architecture is conserved among metazoans to humans, PKB belongs to the species from fly, worm, mouse to man. a glance AGC subfamily of the protein kinase Both the central kinase domain and the Elisabeth Fayard*, Lionel A. superfamily, which consists of 518 HM are highly conserved among AGC members in humans (Manning et al., members, such as , Tintignac*, Anne Baudry and 2002). PKB and v-AKT were first cloned ribosomal p90 S6 kinase, serum- and Brian A. Hemmings‡ in 1991 by three independent groups glucocorticoid-induced kinase, and p70 Friedrich Miescher Institute for Biomedical (Brazil and Hemmings, 2001), more than S6 kinase, mediators of responses Research, Maulbeerstrasse 66, 4058 Basel, Switzerland a decade after the original identification triggered by and/or other growth *These authors contributed equally to this work of transforming murine leukemia virus factors. Interestingly, the PH domain, ‡Author for correspondence Akt8 (Staal et al., 1977). The PKB essential for binding to lipids such as (e-mail: [email protected]) subfamily comprises three mammalian PtdIns(3,4,5)P3, is absent in the S. ␣ ␤ ␥ Journal of Cell Science 118, 5675-5678 isoforms, PKB , PKB and PKB cerevisiae orthologue (Sch9). Published by The Company of Biologists 2005 (Akt1, Akt2 and Akt3, respectively), doi:10.1242/jcs.02724 which are products of distinct genes and share a conserved structure that includes PKB regulation Among the signalling proteins that three functional domains: an N-terminal The key role of PKB in signalling respond to a large variety of signals, pleckstrin homology (PH) domain, a became obvious when it was shown (PKB, also known as central kinase domain, and a C-terminal to be a downstream component Akt) appears to be a central player in regulatory domain containing the in phosphoinositide (PI) 3-kinase regulation of , cell survival, hydrophobic motif (HM) signalling, which is activated upon (1) motility, and cell-cycle site [FxxF(S/T)Y] (Hanada et al., 2004). autophosphorylation of tyrosine

Protein Kinase B/Akt at a Glance Elisabeth Fayard, Lionel A. Tintignac, Anne Baudry and Brian A. Hemmings

PKB-knockout mice PKB signalling in cancer Targeted isoform Survival Phenotype Cancer type Type of alteration

PKBα/AKT1 GF PKBα/AKT2 Integrin GFR PKBα/AKT3

PTEN PKBα/AKT1 PKBβ/AKT2 SHIP P P wortmannin LY294002 PtdIns GPCR (4,5)P SHC 2 P P P P P P85 P110 (3 tdIn Grb2 ,4 s PtdIns P ,5) P CTMP P P P P (3,4,5)P Plasma membrane 3 PtdIns 3

Journal of Cell Science P ? (3,4,5)P TRB3 Paxillin SOS 3 P P P Keratin 10 P P Activity Identified S473 Activity FAK Ras T308 T308 x1000 upstream PI3K x100 P P LY492002 PDK1 DNA-PK LY492002 Independent activation TORC2 i.e. stimulus-specific, LY492002 ATM cell-type-specific S473 S473 ␤ P PKC II , Hsp27, MAPKAP-K2 PKB ternary structure Grb10, Ft1

PKB family phylogeny

Nematode 2 Nematode 1 eNOS Human 1 Caw Rat 1 Mouse 1

Chicken tion P Clawed frog a WNK1 loc

Zebrafish s

Human 2 n Rat 2 a P

Tr IRS1 Mouse 2 Mouse 3 Rat 3 Human 3 6-PF2K Fruitfly Mosquito Metabolism PP2A n Inactivatio TSC2 PKB family structure Inactive e PH PHLPP as Thr-308Ser-473 P P GSK3 Kin PKB␣/Akt1 PH Kinase domain HM 480 HM Thr-309 Ser-474 IKK? BRF1 jcs.biologists.org P P FOXO1 ␤ Kinase domain T PKB /Akt2 PH HM Myt1 ra 481 n s Nuclear export Thr-305 Ser-472 PKB lo c P P a tio PKB␥/Akt3 PH Kinase domain HM n ␬ ␣ ␬ 479 Raf I B NF- B Cytoplasm P P p27* v-Akt Viral gag PH Kinase domain HM 755 Caspase 9* Cytoplasmic retention Nucleus Bad P Bax P NF-␬B Cell growth Symbol Protein synthesis p27* Natural inhibitor of Inhibition of the target upon Transcription Mdm2 the PI3/PKB pathway PKB-mediated phosphorylation Mitochondria p21 Natural activator Activation of the target upon Cell survival FOXO4 FOXO3a of PKB PKB-mediated phosphorylation Degradation Phosphosite identified only in Chemical inhibitor the human protein

Abbreviations: BAD, Bcl2 antagonist of cell death; BRF1, butyrate response factor 1; CTMP, C-terminal modulator protein; DNA PK, DNA-dependent protein kinase; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; FOXO1, -3a, -4, Forkhead Box O1, -3a, -4 (FOXO1/FKHR, FOXO3a/FKHRL1 and FOXO4/AFX); Ft1, fused toes protein 1; GPCR, G-protein-coupled receptor; Grb, receptor bound protein; GSK3, glycogen synthase kinase 3; Hsp27, heat shock protein 27 kDa; Hsp90, heat shock protein 90 kDa; IKK, inhibitor of κ light chain enhancer in B cells; MAPKAP-K2, mitogen activated protein kinase activated protein kinase 2; Mdm2, mouse double minute 2; TORC2, TOR ␬ ␬ (target of rapamycin) complex 2; Myt1, membrane-associated and tyrosine/threonine-specific 1; NF- B, nuclear factor B; PDK1, 3-phosphoinositide-dependent protein kinase; PtdIns(4,5)P2, (4,5)-bisphosphate; PtdIns(3,4,5)P3, phosphatidylinositol (3,4,5)-trisphosphate; PHLPP, PH domain and leucine-rich-repeat protein ; 6-PF2K, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PKC II, protein kinase C isoform beta 2; Plk1, Polo-like kinase1; PP2A, subunit A; Ras, rat sarcoma ; SHC, Src homology 2 domain-containing transforming protein 1; SHIP, SH2-domain-containing inositol polyphosphate 5-phosphatase; SOS, Son of Sevenless.

©Journal of Cell Science 2005 (118, pp. 5675-5678)

(See poster insert) 5676 Journal of Cell Science 118 (24)

kinases induced by ligands (such as depend on the cellular and physiological isoforms still needs to be addressed, but insulin or other growth factors), (2) context. Phosphorylation of Ser473 is recent work on the three knockout mice stimulation of G-protein-coupled the key step in the activation of PKB suggests isoform-specific functions, as receptors, or (3) activation of integrin because it stabilizes the active well as some functional redundancy signalling (Foster et al., 2003; Wymann et conformation state (Yang et al., 2002). (Yang et al., 2004). al., 2003). PI 3-kinase is the key Once activated at the plasma membrane, in the generation of the second messenger phosphorylated PKB can translocate to Genetic manipulation of Pkb genes in PtdIns(3,4,5)P3 from PtdIns(4,5)P2. This the cytosol or the nucleus (Andjelkovic mice, either by transgenic or knockout allows the translocation of PKB from the et al., 1999). approaches, has brought novel insights cytoplasm to the plasma membrane, into PKB signalling (Brazil et al., 2004; which involves its PH domain. Interestingly, a number of PKB-binding Yang et al., 2004 and references therein). Interestingly, artificial targeting of PKB proteins have been shown to modulate These studies identified a wide range of to the plasma membrane, using a PKB activity further in either a positive in vivo functions of PKB, revealing myristoylated/palmitoylated sequence or negative manner. This suggests tissue-specific requirements for the motif fused to the N-terminus of PKB, transient regulation of the kinase by different PKB isoforms in metabolism induces constitutive activation of the adaptator proteins (Brazil et al., 2002; and embryonic development. Various kinase. Once recruited to the plasma Song et al., 2005). Moreover, several transgenic mice expressing membrane, PKB is activated by a multi- negatively regulate PKB constitutively active PKB under the step process that requires phosphorylation activity. The tumor suppressor control of tissue-specific promoters have of both Thr308 in the activation loop of phosphatase and tensin homology been generated. From the analysis of the kinase domain and Ser473 within the deleted on chromosome ten (PTEN) these, it appears that PKB plays a major HM of the regulatory domain. (Stambolic et al., 1998) and role in cell growth: overexpression of Phosphorylation and subsequent the SH2-domain-containing inositol active PKB leads to cardiac or skeletal activation are prevented by the PI 3- polyphosphate 5-phosphatase (SHIP) muscle hypertrophy and an increase in kinase inhibitors wortmannin and (Huber et al., 1999) inhibit PKB activity ␤-cell mass and size, as well as LY294002, both of which are key indirectly by converting PtdIns(3,4,5)P3 potentially promoting the progression of diagnostic reagents for delineating to PtdIns(4,5)P2 and PtdIns(3,4)P2. tumours such as T cell lymphoma or signalling events associated with this Protein phosphatase 2A (PP2A) and PH prostate intraepithelial neoplasia (Lai et pathway. domain leucine-rich repeat protein al., 2004; Yang et al., 2004). phosphatase (PHLPP␣) do so directly by Interestingly, recent results from The serine/threonine kinase phospho- dephosphorylating Ser473 and/or transgenic mice expressing a kinase- inositide-dependent kinase 1 (PDK1), Thr308 on PKB (Andjelkovic et al., dead mutant of PKB␣ in ␤ cells suggest once recruited to the plasma membrane 1996; Gao et al., 2005). Although PKB that it is also involved in the regulation by PtdIns(3,4,5)P3 through its PH is also proposed to be activated in a PI of the insulin secretory pathway (Bernal- Journal of Cell Science domain, is the kinase responsible for the 3-kinase-independent manner Mizrachi et al., 2004). Expression of phosphorylation of Thr308 (Alessi et al., (Vanhaesebroeck and Alessi, 2000), the activated PKB␣ in the mammary gland 1997; Stephens et al., 1998). However, physiological significance of these results in delayed involution and the the identity of the Ser473 kinase findings requires further study. induction of lipid synthesis, leading to an (S473K, also called PDK2) is still increase in milk fat content and lactation controversial. Several candidates have defects (Schwertfeger et al., 2001; been proposed, including PKB itself PKB in physiology Schwertfeger et al., 2003). Finally, (Toker and Newton, 2000), PDK1 To understand the role of PKB, PKB has been shown to exert a (Balendran et al., 1999), integrin-linked tremendous efforts have been made to neuroprotective effect against ischemic kinase 1 (ILK1) (Persad et al., 2001), identify its physiological substrates. brain damage in genetically modified mitogen activated protein kinase PKB has been shown to phosphorylate mice expressing an active form of PKB activated protein kinase 2 (MAPKAP- and regulate the function of many in neuronal cells (Ohba et al., 2004). K2) (Alessi et al., 1996), protein kinase cellular proteins involved in metabolism, C ␤II (PKC␤II) (Kawakami et al., 2004), survival/, differentiation and The Pkb␣/Akt1, Pkb␤/Akt2 or Pkb␥/Akt3 and the members of the atypical PI 3- proliferation (Brazil et al., 2004). Most genes in mice have been targeted by kinase related protein kinase (PIKK) of the PKB substrates contain the homologous recombination. Pkb␣/Akt1 family: DNA-dependent protein kinase minimal consensus sequence deficiency results in significant neonatal (DNA-PK) (Feng et al., 2004), ataxia RxRxx(S/T), where x is any amino acid mortality (Cho et al., 2001; Yang et al., telangiectasia mutant (ATM) (Viniegra and S/T is the phosphorylation site. 2003) and growth retardation due to a et al., 2005) and, more recently, the Interestingly, many of the pathways defect in placental development (Chen et rapamycin-insensitive mTOR complex modulated by PKB are also subject to al., 2001; Cho et al., 2001; Yang et al., TORC2 (Sarbassov et al., 2005). While regulation by other pathways, further 2003). By contrast, Pkb␤/Akt2–/– mice their relative physiological significance highlighting the extreme complexity of display and a type-II- remains to be determined, S473K PKB signalling regulation. The -like syndrome. Furthermore, activity is probably partially redundant interesting issue of the substrate the absence of Pkb␤/Akt2 is and the identity of the kinase might specificities of the different PKB accompanied by mild growth-retardation Cell Science at a Glance 5677

and age-dependent loss of adipose domain-dependent inhibitors have invasion, and metastasis of human breast and tissue. Both Pkb␣/Akt1 and Pkb␤/Akt2 recently been reported to exhibit PKB ovarian cancer cells. Cancer Res. 63, 196-206. Balendran, A., Casamayor, A., Deak, M., are required for normal platelet specificity (Barnett et al., 2005). Paterson, A., Gaffney, P., Currie, R., Downes, aggregation (Chen et al., 2004; Woulfe However, only a subset of the cellular C. P. and Alessi, D. R. (1999). PDK1 acquires et al., 2004). processes regulated by the PI-3- PDK2 activity in the presence of a synthetic kinase–PKB pathway are involved in peptide derived from the carboxyl terminus of Recently, PKB␥ has been shown to play cancer progression. Therefore, the PRK2. Curr. Biol. 9, 393-404. Barnett, S. F., Bilodeau, M. T. and Lindsley, C. an essential role in postnatal brain choice of drug targets should also take W. (2005). The Akt/PKB family of protein –/– development; Pkb␥/Akt3 mice are into account the adverse effects that kinases: a review of small molecule inhibitors and characterized by a 20-25% reduction in could result from the inhibition of other progress towards target validation. Curr. Top. brain size and weight, which is partially PKB-regulated cellular processes, such Med. Chem. 5, 109-125. Bernal-Mizrachi, E., Fatrai, S., Johnson, J. D., due to a decrease in cell size and cell as glucose metabolism, in which Ohsugi, M., Otani, K., Han, Z., Polonsky, K. S. number (Easton et al., 2005; Tschopp et inhibition of PKB potentially leads to a and Permutt, M. A. (2004). Defective insulin al., 2005). Simultaneous inactivation of diabetes-like syndrome (Luo et al., secretion and increased susceptibility to two PKB isoforms in mice leads to a 2005). Furthermore, it is also crucial to experimental diabetes are induced by reduced Akt more severe phenotype: for instance, keep in mind the potentially opposing activity in pancreatic islet beta cells. J. Clin. Invest. ␣ ␤ 114, 928-936. Pkb /Akt1-Pkb /Akt2 double-knockout effects of different PKB isoforms in Brazil, D. P. and Hemmings, B. A. (2001). Ten mutants die immediately after birth and cancer progression. Whereas a reduction years of protein kinase B signalling: a hard Akt to exhibit dwarfism, impairment of in metastasis is observed upon follow. Trends Biochem. Sci. 26, 657-664. adipogenesis and defects in skin, skeletal Pkb␣/Akt1 expression owing to Brazil, D. P., Park, J. and Hemmings, B. A. muscle and bone development (Peng et increased differentiation (Hutchinson et (2002). PKB binding proteins. Getting in on the ␤ Akt. Cell 111, 293-303. al., 2003). Overall, the phenotypic al., 2004) overexpression of Pkb /Akt2 Brazil, D. P., Yang, Z. Z. and Hemmings, B. A. analysis of these mouse models has been associated with invasion and (2004). Advances in protein kinase B signalling: highlights the specific functions of each metastasis (Arboleda et al., 2003). AKTion on multiple fronts. Trends Biochem. Sci. PKB isoform in vivo and the Therefore, pharmaceutical inhibitors 29, 233-242. Chen, J., De, S., Damron, D. S., Chen, W. S., necessity for cells to preserve a crucial specific for each PKB isoform will be Hay, N. and Byzova, T. V. (2004). Impaired level of PKB activity for normal crucial for treatment of diseases that platelet responses to thrombin and collagen in growth, metabolism and differentiation. exhibit abnormal PKB signalling. AKT-1-deficient mice. Blood 104, 1703-1710. Additional combinations of Pkb/Akt Chen, W. S., Xu, P. Z., Gottlob, K., Chen, M. knockout mice should provide further We thank Zhong-Zhou Yang, Bettina Dummler, Banu L., Sokol, K., Shiyanova, T., Roninson, I., Weng, Sürücü and Lana Bozulic for help and critical reading W., Suzuki, R., Tobe, K. et al. (2001). Growth insights in the physiological role of of this manuscript. E.F. and L.A.T. are recipients of retardation and increased apoptosis in mice with PKB. the EMBO long-term post-doctoral fellowships. The homozygous disruption of the Akt1 gene. Genes Friedrich Miescher Institute is part of the Novartis Dev. 15, 2203-2208. Research Foundation. Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F.

Journal of Cell Science PKB deregulation and human and Birnbaum, M. J. (2001). Akt1/PKBalpha is required for normal growth but dispensable for diseases References maintenance of glucose homeostasis in mice. J. A precise understanding of upstream Alessi, D. R., Andjelkovic, M., Caudwell, B., Biol. Chem. 276, 38349-38352. regulators, downstream targets, and in Cron, P., Morrice, N., Cohen, P. and Easton, R. M., Cho, H., Roovers, K., Shineman, vivo functions of PKB should benefit Hemmings, B. A. (1996). Mechanism of D. W., Mizrahi, M., Forman, M. S., Lee, V. M., activation of protein kinase B by insulin and IGF- Szabolcs, M., de Jong, R., Oltersdorf, T. et al. treatment of diseases in which PKB 1. EMBO J. 15, 6541-6551. (2005). Role for Akt3/protein kinase Bgamma in signalling is deregulated, such as cancer Alessi, D. R., James, S. R., Downes, C. P., attainment of normal brain size. Mol. Cell. Biol. 25, and diabetes as well as schizophrenia Holmes, A. B., Gaffney, P. R., Reese, C. B. and 1869-1878. (Nicholson and Anderson, 2002; Cohen, P. (1997). Characterization of a 3- Emamian, E. S., Hall, D., Birnbaum, M. J., Whiteman et al., 2002; Emamian et al., phosphoinositide-dependent protein kinase which Karayiorgou, M. and Gogos, J. A. (2004). phosphorylates and activates protein kinase Convergent evidence for impaired AKT1- 2004). In cancer, constitutive high levels Balpha. Curr. Biol. 7, 261-269. GSK3beta signaling in schizophrenia. Nat. Genet. of PKB activity occur through a variety Andjelkovic, M., Jakubowicz, T., Cron, P., 36, 131-137. of mechanisms, including amplification Ming, X. F., Han, J. W. and Hemmings, B. A. Feng, J., Park, J., Cron, P., Hess, D. and of Pkb/Akt genes and mutations in (1996). Activation and phosphorylation of a Hemmings, B. A. (2004). Identification of a pleckstrin homology domain containing protein PKB/Akt hydrophobic motif Ser-473 kinase as components of the PI 3-kinase signalling kinase (RAC-PK/PKB) promoted by serum and DNA-dependent protein kinase. J. Biol. Chem. pathway, such as PTEN (Luo et al., protein phosphatase inhibitors. Proc. Natl. Acad. 279, 41189-41196. 2003) and the PI 3-kinase subunits. Sci. USA 93, 5699-5704. Foster, F. M., Traer, C. J., Abraham, S. M. and However, constitutive activation of PKB Andjelkovic, M., Maira, S. M., Cron, P., Parker, Fry, M. J. (2003). The phosphoinositide (PI) 3- alone is believed to be insufficient for P. J. and Hemmings, B. A. (1999). Domain kinase family. J. Cell Sci. 116, 3037-3040. swapping used to investigate the mechanism of Gao, T., Furnari, F. and Newton, A. C. (2005). tumorigenesis. It is more likely to protein kinase B regulation by 3-phosphoinositide- PHLPP: a phosphatase that directly contribute to cancer progression by dependent protein kinase 1 and Ser473 kinase. dephosphorylates Akt, promotes apoptosis, and promoting the proliferation, cell survival Mol. Cell. Biol. 19, 5061-5072. suppresses tumor growth. Mol. Cell 18, 13-24. and metabolic capacity of cells. Arboleda, M. J., Lyons, J. F., Kabbinavar, F. F., Hanada, M., Feng, J. and Hemmings, B. A. Bray, M. R., Snow, B. E., Ayala, R., Danino, M., (2004). Structure, regulation and function of Karlan, B. Y. and Slamon, D. J. (2003). PKB/AKT–a major therapeutic target. Biochim. PKB is an attractive therapeutic target Overexpression of AKT2/protein kinase Bbeta Biophys. Acta 1697, 3-16. for treatment of cancer, and novel PH- leads to up-regulation of beta1 integrins, increased Huber, M., Helgason, C. D., Damen, J. E., 5678 Journal of Cell Science 118 (24)

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L., Hahn- Toker, A. and Newton, A. C. (2000). Akt/protein Electronic copies of the poster insert are Windgassen, A., Skeen, J., Jacobs, J., kinase B is regulated by autophosphorylation at the available in the online version of this article Sundararajan, D., Chen, W. S., Crawford, S. E., hypothetical PDK-2 site. J. Biol. Chem. 275, 8271- at jcs.biologists.org. The JPEG images can Coleman, K. G. et al. (2003). Dwarfism, impaired 8274. be downloaded for printing or used as skin development, skeletal muscle atrophy, Tschopp, O., Yang, Z. Z., Brodbeck, D., slides. delayed bone development, and impeded Dummler, B. A., Hemmings-Mieszczak, M.,