Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Perturbations of the AKT signaling pathway in human cancer

Abstract

AKT/PKB (protein kinase B) kinases mediate signaling pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase. AKT kinases regulate diverse cellular processes including cell proliferation and survival, cell size and response to nutrient availability, tissue invasion and angiogenesis. Many oncoproteins and tumor suppressors implicated in cell signaling/metabolic regulation converge within the AKT signal transduction pathway in an equilibrium that is altered in many human cancers by activating and inactivating mechanisms, respectively, targeting these inter-related proteins. We review a burgeoning literature implicating aberrant AKT signaling in many sporadic human cancers as well as in several dominantly inherited cancer syndromes known as phakomatoses. The latter include disorders caused by germline mutations of certain tumor suppressor genes, that is, PTEN, TSC2/TSC1, LKB1, NF1, and VHL, encoding proteins that intersect with the AKT pathway. We also review various pathogenic mechanisms contributing to activation of the AKT pathway in human malignancy as well as current pharmacologic strategies to target therapeutically components of this pathway.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1

References

  • Altomare DA, Tanno S, De Rienzo A, Klein-Szanto A, Skele KL, Hoffman JP and Testa JR . (2003). J. Cell. Biochem., 87, 470–476.

  • Altomare DA, Wang HQ, Skele KL, DeRienzo A, Klein-Szanto AJ, Godwin AK and Testa JR . (2004). Oncogene, 23, 5853–5857.

  • Altomare DA, You H, Xiao GH, Ramos-Nino ME, Skele KL, De Rienzo A, Jhanwar SC, Mossman BT, Kane AB and Testa JR . (2005). Oncogene, 24, 6080–6089.

  • Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R, Danino M, Karlan BY, Slamon DJ, Lee SH, Kim HS, Park WS, Kim SY, Lee KY, Kim SH, Lee JY and Yoo NJ . (2003). Cancer Res., 63, 196–206.

  • Arranz E, Robledo M, Martinez B, Gallego J, Roman A, Rivas C and Benitez J . (1996). Cancer Genet. Cytogenet., 87, 1–3.

  • Astrinidis A and Henske EP . (2005). Oncogene Rev., 24, 7475–7481.

  • Bacus SS, Altomare DA, Lyass L, Chin DM, Farrell MP, Gurova K, Gudkov A and Testa JR . (2002). Oncogene, 21, 3532–3540.

  • Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto AJ, Wang H, Unger M and Testa JR . (2004). Carcinogenesis, 25, 2053–2059.

  • Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V, Ferrandina G, Benedetti Panici P, Mancuso S, Neri G and Testa JR . (1995). Int. J. Cancer, 64, 280–285.

  • Bellacosa A, Kuman CC, Di Cristofano A and Testa JR . (2005). Adv. Cancer Res., 94, 29–86.

  • Bellacosa A, Testa JR, Staal SP and Tsichlis PN . (1991). Science, 254, 274–277.

  • Beuvink I, Boulay A, Fumagalli S, Zibermann F, Ruetz S, O’Reilly T, Natt F, Hall J, Lane HA and Thomas G . (2005). Cell, 120, 747–759.

  • Bjornsti MA and Houghton PJ . (2004). Cancer Cell, 5, 519–523.

  • Boudeau J, Sapkota G and Alessi DR . (2003). FEBS Lett., 546, 159–165.

  • Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O-Reilly T, Stolz B, Marti A, Thomas G and Lane HA . (2004). Cancer Res., 64, 252–261.

  • Brazil DP, Yang ZZ and Hemmings BA . (2004). Trends Biochem. Sci., 29, 233–242.

  • Brognard J, Clark AS, Ni Y and Dennis PA . (2001). Cancer Res., 61, 3986–3997.

  • Byun DS, Cho K, Ryu BK, Lee MG, Park JI, Chae KS, Kim HJ and Chi SG . (2003). Int. J. Cancer, 104, 318–327.

  • Carling D . (2004). Trends Biochem. Sci., 29, 18–24.

  • Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM and Vogt PK . (1997). Science, 276, 1848–1850.

  • Cheng JQ, Altomare DA, Klein MA, Lee W-C, Kruh GD, Lissy NA and Testa JR . (1997). Oncogene, 14, 2793–2801.

  • Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN and Testa JR . (1992). Proc. Natl. Acad. Sci. USA, 89, 9267–9271.

  • Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK and Testa JR . (1996). Proc. Natl. Acad. Sci. USA, 93, 3636–3641.

  • Cheng JQ, Lindsley CW, Cheng GZ, Yang H and Nicosia SV . (2005). Oncogene Rev., 24, 7482–7492.

  • deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, Roth RA and Hidalgo M . (2004). Clin. Cancer Res., 10, 8059–8067.

  • Di Cristofano A and Pandolfi PP . (2000). Cell, 100, 387–390.

  • Di Cristofano A, Pesce B, Cordon-Cardo C and Pandolfi PP . (1998). Nat. Genet., 19, 348–355.

  • Downward J . (2004). Semin. Cell. Dev. Biol., 15, 177–182.

  • Eng C . (2003). Hum. Mutat., 22, 183–198.

  • Greer EL and Brunet A . (2005). Oncogene Rev., 24, 7410–7425.

  • Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN and Larue L . (2003). Cancer Res., 63, 2172–2178.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Hu L, Hofmann J, Lu Y, Mills GB and Jaffe RB . (2002). Cancer Res., 62, 1087–1092.

  • Inoki K, Corradetti MN and Guan KL . (2005). Nat. Genet., 37, 19–24.

  • Inoki K, Zhu T and Guan KL . (2003). Cell, 115, 577–590.

  • Johannessen CM, Reczek EE, James MF, Brems H, Legius E and Cichowski K . (2005). Proc. Natl. Acad. Sci. USA, 102, 8573–8578.

  • Jucker M, Sudel K, Horn S, Sickel M, Wegner W, Fiedler W and Feldman RA . (2002). Leukemia, 16, 894–901.

  • Kang S, Bader AG and Vogt PK . (2005). Proc. Natl. Acad. Sci. USA, 102, 802–807.

  • Kenerson HL, Aicher LD, True LD and Yeung RS . (2002). Cancer Res., 62, 5645–5650.

  • Kim WY and Kaelin WG . (2004). J. Clin. Oncol., 22, 4991–5004.

  • Knobbe CB and Reifenberger G . (2003). Brain Pathol., 13, 507–518.

  • Kumar CC and Madison V . (2005). Oncogene Rev., 24, 7493–7454.

  • Kwiatkowski DJ . (2003). Ann. Hum. Genet., 67, 87–96.

  • Larue L and Bellacosa A . (2005). Oncogene Rev., 24, 7443–7454.

  • Lefranc F, Brotchi J and Kiss R . (2005). J. Clin. Oncol., 23, 2411–2422.

  • Lian Z and Di Cristofano A . (2005). Oncogene Rev., 24, 7394–7400.

  • Liang J and Slingerland JM . (2003). Cell Cycle, 2, 339–345.

  • Liu JP . (1999). FASEB J., 13, 2091–2104.

  • Liu AX, Testa JR, Hamilton TC, Jove R, Nicosia SV and Cheng JQ . (1998). Cancer Res., 58, 2973–2977.

  • Luo J, Manning BD and Cantley LC . (2003). Cancer Cell, 4, 257–262.

  • Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA and Sellers WR . (2004). Nat. Med., 10, 594–601.

  • Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, Xue Q, Bikoff R, Ma H, Kantoff PW, Golub TR, Loda M and Sellers WR . (2003). Proc. Natl. Acad. Sci. USA, 100, 7841–7846.

  • Majumder PK and Sellers WR . (2005). Oncogene Rev., 24, 7465–7474.

  • Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW and Sonenberg N . (2004). Oncogene, 23, 3172–3179.

  • Mayo LD and Donner DB . (2002). Trends Biochem. Sci.,, 27, 462–467.

  • Mitsiades CS, Mitsiades N and Koutsilieris M . (2004). Curr. Cancer Drug Targets, 4, 235–256.

  • Miwa W, Yasuda J, Murakami Y, Yashima K, Sugano K, Sekine T, Kono A, Egawa S, Yamaguchi K, Hayashizaki Y and Sekiya T . (1996). Biochem. Biophys. Res. Commun., 225, 968–974.

  • Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN and Rosen N . (1998). J. Biol. Chem., 273, 29864–29872.

  • Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ and Roth RA . (1999). J. Biol. Chem., 274, 21528–21532.

  • Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H and Sawyers CL . (2001). Proc. Natl. Acad. Sci. USA, 98, 10314–10319.

  • Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M and Lin J . (2000). Anticancer Res., 20, 407–416.

  • Pedrero JM, Carracedo DG, Pinto CM, Zapatero AH, Rodrigo JP, Nieto CS and Gonzalez MV . (2005). Int. J. Cancer, 114, 242–248.

  • Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, Thomas RJ and Phillips WA . (2001). Cancer Res., 61, 7426–7429.

  • Plas DR and Thompson CB . (2005). Oncogene Rev., 24, 7435–7442.

  • Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P, Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C, Hedrick-Ellenson L and Parsons R . (2001). Proc. Natl. Acad. Sci. USA, 98, 10320–10325.

  • Pommier Y, Sordet O, Antony S, Hayward RL and Kohn KW . (2004). Oncogene, 23, 2934–2949.

  • Robertson GP . (2005). Cancer Met Rev., 24, 273–285.

  • Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT and Smyrk TC . (2002). Carcinogenesis, 23, 201–205.

  • Ruggeri BA, Huang L, Wood M, Cheng JQ and Testa JR . (1998). Mol. Carc., 21, 81–86.

  • Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C and Pandolfi PP . (2004). Nat. Med., 10, 484–486.

  • Ruggero D and Pandolfi PP . (2003). Nat. Rev. Cancer, 3, 179–192.

  • Ruggero D and Sonenberg N . (2005). Oncogene Rev., 24, 7426–7434.

  • Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A and Parsons R . (2005). Cancer Res., 65, 2554–2559.

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B and Velculescu VE . (2004). Science, 304, 554.

  • Sansal I and Sellers WR . (2004). J. Clin. Oncol., 22, 2954–2963.

  • Scheid MP and Woodgett JR . (2003). FEBS Lett., 546, 108–112.

  • Schlegel J, Piontek G and Mennel HD . (2002). Anticancer Res., 22, 2837–2840.

  • Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA and Cantley LC . (2004). Cancer Cell, 6, 91–99.

  • Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB and Gray JW . (1999). Nat. Genet., 21, 99–102.

  • Shiojima I and Walsh K . (2002). Circ. Res., 90, 1243–1250.

  • Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN and Calabretta B . (1997). EMBO J., 16, 6151–6161.

  • Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L, Morris SW, Wasik MA and Skorski T . (2001). Cancer Res., 61, 2194–2199.

  • Sordella R, Bell DW, Haber DA and Setteman J . (2004). Science, 305, 1163–1167.

  • Staal SP . (1987). Proc. Natl. Acad. Sci. USA, 84, 5034–5037.

  • Stal O, Perez-Tenorio G, Akerberg L, Olsson B, Nordenskjold B, Skoog L and Rutqvist LE . (2003). Breast Cancer Res., 5, R37–R44.

  • Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL, Shelley SA, Jove R, Tsichlis PN, Nicosia SV and Cheng JQ . (2001). Am. J. Pathol., 159, 431–437.

  • Sun S and Steinberg BM . (2002). J. Gen. Virol., 83, 1651–1658.

  • Tanno S, Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH and Testa JR . (2001). Cancer Res., 61, 589–593.

  • Terakawa N, Kanamori Y and Yoshida S . (2003). Endocr. Relat. Cancer, 10, 203–208.

  • Testa JR and Bellacosa A . (2001). Proc. Natl. Acad. Sci. USA, 98, 10983–10985.

  • Thant AA, Nawa A, Kikkawa F, Ichigotani Y, Zhang Y, Sein TT, Amin AR and Hamaguchi M . (2000). Clin. Exp. Metastasis, 18, 423–428.

  • Thompson FH, Nelson MA, Trent JM, Guan XY, Liu Y, Yang JM, Emerson J, Adair L, Wymer J, Balfour C, Massey K, Weinstein R, Alberts DS and Taetle R . (1996). Cancer Genet. Cytogenet., 87, 55–62.

  • Tsao AS, McDonnell T, Lam S, Putnam JB, Bekele N, Hong WK and Kurie JM . (2003). Cancer Epidemiol. Biomarkers Prev., 12, 660–664.

  • Tucker M, Goldstein A, Dean M and Knudson A . (2000). J. Natl. Cancer Inst., 92, 530–533.

  • Waldmann V, Wacker J and Deichmann M . (2001). Arch. Dermatol. Res., 293, 368–372.

  • Wendel HG, DeStanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J and Lowe SW . (2004). Nature, 428, 267–269.

  • Whang YE, Yuan XJ, Liu Y, Majumder S and Lewis TD . (2004). Vitamins Hormones, 67, 409–426.

  • Whiteman EL, Cho H and Birnbaum MJ . (2002). Trends Endocrinol. Metab., 13, 444–451.

  • Xu X, Sakon M, Nagano H, Hiraoka N, Yamamoto H, Hayashi N, Dono K, Nakamori S, Umeshita K, Ito Y, Matsuura N and Monden M . (2004). Oncol. Rep., 11, 25–32.

  • Yang L, Dan HC, Sun M, Liu QY, Sun XM, Feldman RI, Hamilton AD, Polokoff M, Nicosia SV, Herlyn M, Sebti SM and Cheng JQ . (2004). Cancer Res., 64, 4394–4399.

  • Yuan ZQ, Sun M, Feldman RI, Wang G, Ma X, Jiang C, Coppola D, Nicosia SV and Cheng JQ . (2000). Oncogene, 19, 2324–2330.

  • Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL and Kwiatkowski DJ . (2003). J. Clin. Invest., 112, 1223–1233.

  • Zhou BP and Hung MC . (2002). Semin. Oncol., 29, 62–70.

Download references

Acknowledgements

This work was supported by NIH Grants CA77429, CA83638 (SPORE in Ovarian Cancer), and CA06927, and by an appropriation from the Commonwealth of Pennsylvania to the Fox Chase Cancer Center.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joseph R Testa.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Altomare, D., Testa, J. Perturbations of the AKT signaling pathway in human cancer. Oncogene 24, 7455–7464 (2005). https://doi.org/10.1038/sj.onc.1209085

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209085

Keywords

  • AKT/PKB kinases
  • tumor suppressor genes
  • oncogenes
  • human malignancy
  • targeted therapy

This article is cited by

Search

Quick links