Akt1 and Akt2: Differentiating the action

Histology and Histopathology

Volumn 26, Issue 5, 2011, Pages 651-662

  Heron Milhavet, Lisa ^a   Khouya, Nabil ^a   Fernandez, Anne ^a   Lamb, Ned J ^a  

^a INSTITUTE OF HUMAN GENETICS   (France)

Author keywords

Akt isoforms; Cancer; Differentiation; Metastasis; Migration; Proliferation

Indexed keywords

INSULIN; ISOPROTEIN; PROTEIN KINASE B;

AMINO ACID SEQUENCE; ANIMAL; CELL DIFFERENTIATION; CELL PROLIFERATION; GENE EXPRESSION REGULATION; HUMAN; METABOLISM; METASTASIS; MOLECULAR GENETICS; MOUSE; MOUSE MUTANT; NEOPLASM; REVIEW; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANIMALS; CELL DIFFERENTIATION; CELL PROLIFERATION; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; INSULIN; MICE; MICE, KNOCKOUT; MOLECULAR SEQUENCE DATA; NEOPLASM METASTASIS; NEOPLASMS; PROTEIN ISOFORMS; PROTO-ONCOGENE PROTEINS C-AKT; SEQUENCE HOMOLOGY, AMINO ACID; SIGNAL TRANSDUCTION;

EID: 79960638332     PISSN: 02133911     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (77)

1. Aktas B., Tewes M., Fehm T., Hauch S., Kimmig R. and Kasimir-Bauer S. (2009). Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 11, R46.
2. Alessi D.R., Caudwell F.B., Andjelkovic M., Hemmings B.A. and Cohen P. (1996). Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 399, 333-338.
3. Alessi D.R., James S.R., Downes C.P., Holmes A.B., Gaffney P.R., Reese C.B. and Cohen P. (1997). Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr. Biol. 7, 261-269.
4. Altomare D.A., You H., Xiao G.H., Ramos-Nino M.E., Skele K.L., De Rienzo A., Jhanwar S.C., Mossman B.T., Kane A.B. and Testa J.R. (2005). Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene 24, 6080-6089.
5. Andjelkoviç M., Alessi D.R., Meier R., Fernandez A., Lamb N.J., Frech M., Cron P., Cohen P., Lucocq J.M. and Hemmings B.A. (1997). Role of translocation in the activation and function of protein kinase B. J. Biol. Chem. 272, 31515-31524.
6. Arboleda M.J., Lyons J.F., Kabbinavar F.F., Bray M.R., Snow B.E., Ayala R., Danino M., Karlan B.Y. and Slamon D.J. (2003). Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res. 63, 196-206.
7. Barnett S.F., Defeo-Jones D., Fu S., Hancock P.J., Haskell K.M., Jones R.E., Kahana J.A., Kral A.M., Leander K., Lee L.L., Malinowski J., McAvoy E.M., Nahas D.D., Robinson R.G. and Huber H.E. (2005). Identification and characterization of pleckstrin-homology-domaindependent and isoenzyme-specific Akt inhibitors. Biochem. J. 385, 399-408.
8. Bayascas J.R., Wullschleger S., Sakamoto K., García-Martínez J.M., Clacher C., Komander D., van Aalten D.M., Boini K.M., Lang F., Lipina C., Logie L., Sutherland C., Chudek J.A., van Diepen J.A., Voshol P.J., Lucocq J.M. and Alessi D.R. (2008). Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Mol. Cell. Biol. 28, 3258-3272.
9. Carpten J.D., Faber A.L., Horn C., Donoho G.P., Briggs S.L., Robbins C.M., Hostetter G., Boguslawski S., Moses T.Y., Savage S., Uhlik M., Lin A., Du J., Qian Y.W., Zeckner D.J., Tucker-Kellogg G., Touchman J., Patel K., Mousses S., Bittner M., Schevitz R., Lai M.H., Blanchard K.L. and Thomas J.E. (2007). A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439-444.
10. Chen W.S., Xu P.Z., Gottlob K., Chen M.L., Sokol K., Shiyanova T., Roninson I., Weng W., Suzuki R., Tobe K., Kadowaki T. and Hay N. (2001). Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 15, 2203-2208.
11. Chin Y.R. and Toker A. (2010). The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol. Cell. 38, 333-344.
12. Cho H., Thorvaldsen J.L., Chu Q., Feng F. and Birnbaum M.J. (2001a). Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349-38352.
13. Cho H., Mu J., Kim J.K., Thorvaldsen J.L., Chu Q., Crenshaw E.B. 3rd, Kaestner K.H., Bartolomei M.S., Shulman G.I. and Birnbaum M.J. (2001). Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292, 1728-1731.
14. Cicenas J. (2008). The potential role of Akt phosphorylation in human cancers. Int. J. Biol. Markers 23, 1-9.
15. Davies M.A., Stemke-Hale K., Tellez C., Calderone T.L., Deng W., Prieto V.G., Lazar A.J., Gershenwald J.E. and Mills G.B. (2008). A novel AKT3 mutation in melanoma tumours and cell lines. Br. J. Cancer 99, 1265-1268.
16. DeFeo-Jones D., Barnett S.F., Fu S., Hancock P.J., Haskell K.M., Leander K.R., McAvoy E., Robinson R.G., Duggan M.E., Lindsley C.W., Zhao Z., Huber H.E. and Jones R.E. (2005). Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members. Mol. Cancer Ther. 4, 271-279.
17. Dillon R.L., Marcotte R., Hennessy B.T., Woodgett J.R., Mills G.B. and Muller W.J. (2009). Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Res. 69, 5057-5064.
18. Franke T.F. (2008). PI3K/Akt: getting it right matters. Oncogene 27, 6473-6488.
19. Franke T.F. and Cantley L.C. (1997). Apoptosis. A Bad kinase makes good. Nature 390, 116-117.
20. Garrett C.R., Coppola D., Wenham R.M., Cubitt C.L., Neuger A.M., Frost T.J., Lush R.M., Sullivan D.M., Cheng J.Q. and Sebti S.M. (2010). Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest. New Drugs (in press).
21. Garofalo R.S., Orena S.J., Rafidi K., Torchia A.J., Stock J.L., Hildebrandt A.L. Coskran T., Black S.C., Brees D.J., Wicks J.R., McNeish J.D. and Coleman K.G. (2003). Severe diabetes, agedependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J. Clin. Invest. 112, 197-208.
22. Gherzi R., Trabucchi M., Ponassi M., Gallouzi I.E., Rosenfeld M.G. and Briata P. (2010). Akt2-mediated phosphorylation of Pitx2 controls Ccnd1 mRNA decay during muscle cell differentiation. Cell Death Differ. 17, 975-983.
23. Grille S.J., Bellacosa A., Upson J., Klein-Szanto AJ., van Roy F., Lee-Kwon W., Donowitz M., Tsichlis P.N. and Larue L. (2003). The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 63, 2172-2178.
24. Han E.K., Mcgonigal T., Butler C., Giranda V.L. and Luo Y. (2008). Characterization of Akt overexpression in MiaPaCa-2 cells: prohibitin is an Akt substrate both in vitro and in cells. Anticancer Res. 28, 957-963.
25. Héron-Milhavet L., Franckhauser C., Rana V., Berthenet C., Fisher D., Hemmings B.A., Fernandez A. and Lamb N.J. (2006). Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol. Cell. Biol. 26, 8267-8280.
26. Heron-Milhavet L., Mamaeva D., LeRoith D., Lamb N.J. and Fernandez A. (2010). Impaired muscle regeneration and myoblast differentiation in mice with a muscle-specific KO of IGF-IR. J. Cell. Physiol. 225, 1-6.
27. Higuchi M., Masuyama N., Fukui Y., Suzuki A. and Gotoh Y. (2001). Akt mediates Rac/Cdc42-regulated cell motility in growth factorstimulated cells and in invasive PTEN knockout cells. Curr. Biol. 11, 1958-1962.
28. Hill M.M., Clark S.F., Tucker D.F., Birnbaum M.J., James D.E. and Macaulay S.L. (1999). A role for protein kinase Bbeta/Akt2 in insulinstimulated GLUT4 translocation in adipocytes. Mol. Cell. Biol. 19, 7771-7781.
29. Hirano I., Nakamura S., Yokota D., Ono T., Shigeno K., Fujisawa S., Shinjo K. and Ohnishi K. (2009). Depletion of Pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 by Bcr-Abl promotes chronic myelogenous leukemia cell proliferation through continuous phosphorylation of Akt isoforms. J. Biol. Chem. 284, 22155-22165.
30. Hutchinson J.N., Jin J., Cardiff R.D., Woodgett J.R. and Muller W.J. (2004). Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res. 64, 3171-3178.
31. Hwang S.K., Lim H.T., Minai-Tehrani A., Lee E.S., Park J., Park S.B., Beck G.R. Jr and Cho M.H. (2009). Repeated aerosol delivery of carboxyl-terminal modulator protein suppresses tumor in the lungs of K-rasLA1 mice. Am. J. Respir. Crit. Care Med. 179, 1131-1140.
32. Iliopoulos D., Polytarchou C., Hatziapostolou M., Kottakis F., Maroulakou I.G., Struhl K. and Tsichlis P.N. (2009). MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci. Signal. 2, ra62.
33. Irie H.Y., Pearline R.V., Grueneberg D., Hsia M., Ravichandran P., Kothari N., Natesan S. and Brugge J.S. (2005). Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J. Cell. Biol. 171, 1023-1034.
34. Julien S., Puig I., Caretti E., Bonaventure J., Nelles L., van Roy F., Dargemont C., de Herreros A.G., Bellacosa A. and Larue L. (2007). Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26, 7445-7456.
35. Katome T., Obata T., Matsushima R., Masuyama N., Cantley L.C., Gotoh Y., Kishi K., Shiota H. and Ebina Y. (2003). Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions. J. Biol. Chem. 278, 28312-28323.
36. Kim I.A., Bae S.S., Fernandes A., Wu J., Muschel R.J., McKenna W.G., Birnbaum M.J. and Bernhard E.J. (2005). Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res. 65, 7902-7910.
37. Kim E.K., Tucker D.F., Yun S.J., Do K.H., Kim M.S., Kim J.H., Kim C.D., Birnbaum M.J. and Bae S.S. (2008). Linker region of Akt1/protein kinase Balpha mediates platelet-derived growth factor-induced translocation and cell migration. Cell. Signal. 20, 2030-2037.
38. Kim D., Sun M., He L., Zhou Q.H., Chen J., Sun X.M., Bepler G., Sebti S.M. and Cheng J.Q. (2010). A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation. J. Biol. Chem. 285, 8383-8394.
39. Kirkegaard T., Witton C.J., Edwards J., Nielsen K.V., Jensen L.B., Campbell F.M., Cooke T.G. and Bartlett J.M. (2010). Molecular alterations in AKT1, AKT2 and AKT3 detected in breast and prostatic cancer by FISH. Histopathology 56, 203-211.
40. Knobbe C.B., Reifenberger J., Blaschke B. and Reifenberger G. (2004). Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J. Natl. Cancer Inst. 96, 483-486.
41. Lin Y., Wang Z., Liu L. and Chen L. (2011). Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells. Lung Cancer 71, 291-297.
42. Liu P., Cheng H., Roberts T.M. and Zhao J.J. (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627-644.
43. Maira S.M., Galetic I., Brazil D.P., Kaech S., Ingley E., Thelen M. and Hemmings B.A. (2001). Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-akt at the plasma membrane. Science 294, 374-380.
44. Manning B.D. and Cantley L.C. (2007). AKT/PKB signaling: navigating downstream. Cell 129, 1261-1274.
45. Maroulakou I.G., Oemler W., Naber S.P. and Tsichlis P.N. (2007). Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res. 67, 167-177.
46. Maroulakou I.G., Oemler W., Naber S.P., Klebba I., Kuperwasser C. and Tsichlis P.N. (2008). Distinct roles of the three Akt isoforms in lactogenic differentiation and involution. J. Cell. Physiol. 217, 468-477.
47. Mure H., Matsuzaki K., Kitazato K.T., Mizobuchi Y., Kuwayama K., Kageji T. and Nagahiro S. (2010). Akt2 and Akt3 play a pivotal role in malignant gliomas. Neuro. Oncol. 12, 221-232.
48. O'Shaughnessy R.F., Akgül B., Storey A., Pfister H., Harwood C.A. and Byrne C. (2007). Cutaneous human papillomaviruses down-regulate AKT1, whereas AKT2 up-regulation and activation associates with tumors. Cancer Res. 67, 8207-8215.
49. Parcellier A., Tintignac L.A., Zhuravleva E., Cron P., Schenk S., Bozulic L. and Hemmings B.A. (2009). Carboxy-Terminal Modulator Protein (CTMP) is a mitochondrial protein that sensitizes cells to apoptosis. Cell. Signal. 21, 639-650.
50. Peng X.D., Xu P.Z., Chen M.L., Hahn-Windgassen A., Skeen J., Jacobs J., Sundararajan D., Chen W.S., Crawford S.E., Coleman K.G. and Hay N. (2003). Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev. 17, 1352-1365.
51. Piao L., Li Y., Yang K.J., Park K.A., Byun H.S., Won M., Hong J., Kim J.L., Kweon G.R., Hur G.M., Seok J.H., Cho J.Y., Chun T., Hess D., Sack R., Maira S.M., Brazil D.P., Hemmings B.A. and Park J. (2009). Heat shock protein 70-mediated sensitization of cells to apoptosis by Carboxyl-Terminal Modulator Protein. BMC Cell. Biol. 10, 53.
52. Pollack I.F., Hamilton R.L., Burger P.C., Brat D.J., Rosenblum M.K., Murdoch G.H., Nikiforova M.N., Holmes E.J., Zhou T., Cohen K.J. and Jakacki R.I. (2010). Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children's Oncology Group. J. Neurooncol. 99, 155-163.
53. Ptaszynska M.M., Pendrak M.L., Stracke M.L. and Roberts D.D. (2010). Autotaxin signaling via lysophosphatidic acid receptors contributes to vascular endothelial growth factor-induced endothelial cell migration. Mol. Cancer Res. 8, 309-321.
54. Qiao M., Iglehart J.D. and Pardee A.B. (2007). Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation. Cancer Res. 67, 5293-5299.
55. Restuccia D.F. and Hemmings B.A. (2010). From man to mouse and back again: advances in defining tumor AKTivities in vivo. Dis. Model. Mech. 3, 705-720.
56. Safi A., Vandromme M., Caussanel S., Valdacci L., Baas D., Vidal M., Brun G., Schaeffer L. and Goillot E. (2004) Role for the pleckstrin homology domain-containing protein CKIP-1 in phosphatidylinositol 3-kinase-regulated muscle differentiation. Mol. Cell. Biol. 24, 1245-1255.
57. Santi S.A. and Lee H. (2010). The Akt isoforms are present at distinct subcellular locations. Am. J. Physiol. Cell. Physiol. 298, C580-591.
58. Sarbassov D.D., Guertin D.A., Ali S.M. and Sabatini D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101.
59. Shen X., Xi G., Radhakrishnan Y. and Clemmons D.R. (2010). PDK1 Recruitment to the SHPS-1 Signaling Complex Enhances Insulinlike Growth Factor-I-stimulated AKT Activation and Vascular Smooth Muscle Cell Survival. J. Biol. Chem. 285, 29416-29424.
60. Sievers C., Billig G., Gottschalk K. and Rudel T. (2010). Prohibitins are required for cancer cell proliferation and adhesion. PLoS One 5, e12735.
61. Simon P.O. Jr, McDunn J.E., Kashiwagi H., Chang K., Goedegebuure P.S., Hotchkiss R.S. and Hawkins W.G. (2009). Targeting AKT with the proapoptotic peptide, TAT-CTMP: a novel strategy for the treatment of human pancreatic adenocarcinoma. Int. J. Cancer 125, 942-951.
62. Staal S.P., Hartley J.W. and Rowe W.P. (1977). Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proc. Natl. Acad. Sci. USA 74, 3065-3067.
63. Sun M., Wang G., Paciga J.E., Feldman R.I., Yuan Z.Q., Ma X.L., Shelley S.A., Jove R., Tsichlis P.N., Nicosia S.V. and Cheng J.Q. (2001). AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am. J. Pathol. 159, 431-437.
64. Toker A. and Yoeli-Lerner M. (2006). Akt signaling and cancer: surviving but not moving on. Cancer Res. 66, 3963-3966.
65. Tokuda E., Fujita N., Oh-hara T., Sato S., Kurata A., Katayama R., Itoh T., Takenawa T., Miyazono K. and Tsuruo T. (2007). Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domaininteracting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo. Cancer Res. 67, 9666-9676.
66. Tschopp O., Yang Z.Z., Brodbeck D., Dummler B.A., Hemmings-Mieszczak M., Watanabe T., Michaelis T., Frahm J. and Hemmings B.A. (2005). Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132, 2943-2954.
67. Vandromme M., Rochat A., Meier R., Carnac G., Besser D., Hemmings B.A., Fernandez A. and Lamb N.J. (2001). Protein kinase B beta/Akt2 plays a specific role in muscle differentiation. J. Biol. Chem. 276, 8173-8179.
68. Vivanco I. and Sawyers C.L. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501.
69. Wang S. and Basson M.D. (2008). Identification of functional domains in AKT responsible for distinct roles of AKT isoforms in pressurestimulated cancer cell adhesion. Exp. Cell Res. 314, 286-296.
70. Wickenden J.A. and Watson C.J. (2010). Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts. Breast Cancer Res. 12, 202.
71. Yang J., Cron P., Thompson V., Good V.M., Hess D., Hemmings B.A. and Barford D. (2002). Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell 9, 1227-1240.
72. Yang Z.Z., Tschopp O., Di-Poï N., Bruder E., Baudry A., Dümmler B., Wahli W. and Hemmings B.A. (2005). Dosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice. Mol. Cell. Biol. 25, 10407-10418.
73. Yoeli-Lerner M., Yiu G.K., Rabinovitz I., Erhardt P., Jauliac S. and Toker A. (2005). Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol. Cell 20, 539-550.
74. Zhao Z., Leister W.H., Robinson R.G., Barnett S.F., Defeo-Jones D., Jones R.E., Hartman G.D., Huff J.R., Huber H.E., Duggan M.E. and Lindsley C.W. (2005). Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors. Bioorg. Med. Chem. Lett. 15, 905-909.
75. Zhao Z., Robinson R.G., Barnett S.F., Defeo-Jones D., Jones R.E., Hartman G.D., Huber H.E., Duggan M.E. and Lindsley C.W. (2008). Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity. Bioorg. Med. Chem. Lett. 18, 49-53.
76. Zheng Y., Peng M., Wang Z., Asara J.M. and Tyner A.L. (2010). Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor. Mol. Cell. Biol. 30, 4280-4292.
77. Zhou G.L., Tucker D.F., Bae S.S., Bhatheja K., Birnbaum M.J. and Field J. (2006). Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J. Biol. Chem. 281, 36443-36453.