The role of PI3K/AKT/FOXO signaling in psoriasis

  • Miao Zhang
  • Xiaoyan ZhangEmail author


Phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway play a central role in multiple cellular functions such as cell proliferation and survival. The forkhead box O (FOXO) transcription factors are negatively regulated by the PI3K/AKT signaling pathway and considered to have inhibitory effect on cell proliferation. Psoriasis is a multifactorial disease with a strong genetic background and characterized by hyperproliferative keratinocyte. PI3K signaling regulates proliferation of keratinocyte by activating AKT and other targets, and by inducing FOXO downregulation. The amplification of PI3K and AKT and the loss of the FOXO are gradually being recognized in psoriatic lesions. The upstream and downstream of PI3K/AKT signaling molecules such as tumor suppressor phosphatase and tensin homolog (PTEN) and mammalian target of Rapamycin (mTOR), respectively, are also frequently altered in psoriasis. In this review, we highlight the recent studies on the roles and mechanisms of PI3K and AKT in regulating hyperproliferation of keratinocyte, and the roles of the downstream targets FOXO in psoriasis. Finally, we summarized that PI3K/AKT/FOXO signaling and its upstream and downstream molecule which could be underlying therapeutic target for psoriasis. This article is part of a special issue entitled: PI3K–AKT–FOXO axis in psoriasis.


PI3K AKT FOXO Psoriasis PTEN mTOR Hyperproliferation of keratinocyte Psoriatic lesions Inhibitor 



Phosphatidylinositol-4,5-bisphosphate 3-kinase


Protein kinase B


Forkhead box O


Phosphatase and tensin homolog


Mammalian target of Rapamycin complex


Phosphoinositide-dependent kinase-1


Growth factor receptor


Pleckstrin homology


Phosphatidylinositol 3–5 triphosphate


Acute-lymphocytic-leukemia-1 fused gene from chromosome X


Forkhead in rhabdomyosarcoma


FKHR-like 1


Interleukin 22


Fas ligand


TNF-related apoptosis-inducing ligand


TNF receptor type 1 associated death domain


B-cell lymphoma 2


Bcl-2-like protein 11


Bcl-2-associated death promoter


Synovial cells


Normal human epidermal keratinocyte




Reactive oxygen species



This work was supported by a grant from the National Natural Science Foundation of China (Grant numbers: 81573048).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

This article does not contain any studies with human participants or animals performed by any of the authors; therefore, informed consent is not applicable.


  1. 1.
    Aksamitiene E, Kiyatkin A, Kholodenko BN (2012) Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans 40:139–146PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R et al (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11:R46PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Albert V, Hall MN (2015) mTOR signaling in cellular and organismal energetics. Curr Opin Cell Biol 33:55–66PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Amin AG, Wang A, Braun A, Tobias M, Murali R et al (2017) Abstract 3125: Therapeutic implications of mTORC1 and mTORC2 inhibitors in genetically heterogeneous glioblastoma. Can Res 77:3125–3125CrossRefGoogle Scholar
  5. 5.
    Balato A, Caprio RD, Lembo S, Mattii M, Megna M et al (2014) Mammalian target of rapamycin in inflammatory skin conditions. Eur J Inflamm 12:341–350CrossRefGoogle Scholar
  6. 6.
    Balato A, Lembo S, Ayala F, Balato N, Caiazzo G et al (2017) Mechanistic target of rapamycin complex 1 is involved in psoriasis and regulated by anti-TNF-alpha treatment. Exp Dermatol 26:325–327PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Bao S, Ouyang G, Bai X, Huang Z, Ma C et al (2004) Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell 5:329–339PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Birkenkamp KU, Coffer PJ (2003) Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. Biochem Soc Trans 31:292–297PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Bradley AW, James ED, Charles JM (2011) New organ-specific pharmacological strategies interfering with signaling pathways in inflammatory disorders/autoimmune disorders. Curr Signal Transduct Ther 6:279–291CrossRefGoogle Scholar
  10. 10.
    Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26:657–664PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D et al (2002) 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol 156:817–828PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Buerger C, Malisiewicz B, Eiser A, Hardt K, Boehncke WH (2013) Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin. Br J Dermatol 169:156–159PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Buerger C, Shirsath N, Lang V, Berard A, Diehl S et al (2017) Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation. PLoS One 12:e0180853PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Burger C, Shirsath N, Lang V, Diehl S, Kaufmann R et al (2017) Blocking mTOR Signalling with Rapamycin ameliorates Imiquimod-induced Psoriasis in Mice. Acta Derm Venereol 97:1087–1094PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Burgering BM (2008) A brief introduction to FOXOlogy. Oncogene 27:2258–2262PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Burgering BM, Kops GJ (2002) Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27:352–360PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Burgering BM, Medema RH (2003) Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 73:689–701PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Calautti E, Li J, Saoncella S, Brissette JL, Goetinck PF (2005) Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. J Biol Chem 280:32856–32865PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Carracedo A, Alimonti A, Pandolfi PP (2011) PTEN level in tumor suppression: how much is too little? Cancer Res 71:629–633PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Chamcheu JC, Adhami VM, Esnault S, Sechi M, Siddiqui IA et al (2017) Dual Inhibition of PI3K/Akt and mTOR by the dietary antioxidant, delphinidin, ameliorates psoriatic features in vitro and in an imiquimod-induced psoriasis-like disease in mice. Antioxid Redox Signal 26:49–69PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Chamcheu JC, Chaves-Rodriquez MI, Adhami VM, Siddiqui IA, Wood GS et al (2016) Upregulation of PI3K/AKT/mTOR, FABP5 and PPARbeta/delta in human psoriasis and imiquimod-induced murine psoriasiform dermatitis model. Acta Derm Venereol 96:854–856PubMedPubMedCentralGoogle Scholar
  25. 25.
    Chamcheu JC, Pal HC, Siddiqui IA, Adhami VM, Ayehunie S et al (2015) Prodifferentiation, anti-inflammatory and antiproliferative effects of delphinidin, a dietary anthocyanidin, in a full-thickness three-dimensional reconstituted human skin model of psoriasis. Skin Pharmacol Physiol 28:177–188PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Chen L, Wu J, Pier E, Zhao Y, Shen Z (2013) mTORC2-PKBalpha/Akt1 Serine 473 phosphorylation axis is essential for regulation of FOXP3 stability by chemokine CCL3 in psoriasis. J Invest Dermatol 133:418–428PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Chen SJ, Nakahara T, Takahara M, Kido M, Dugu L et al (2009) Activation of the mammalian target of rapamycin signalling pathway in epidermal tumours and its correlation with cyclin-dependent kinase 2. Br J Dermatol 160:442–445PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Christophers E (2001) Psoriasis–epidemiology and clinical spectrum. Clin Exp Dermatol 26:314–320CrossRefGoogle Scholar
  29. 29.
    Coffre M, Benhamou D, Riess D, Blumenberg L, Snetkova V et al (2016) miRNAs are essential for the regulation of the PI3K/AKT/FOXO pathway and receptor editing during B cell maturation. Cell Rep 17:2271–2285PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Datta Mitra A, Raychaudhuri SP, Abria CJ, Mitra A, Wright R et al (2013) 1alpha,25-Dihydroxyvitamin-D3-3-bromoacetate regulates AKT/mTOR signaling cascades: a therapeutic agent for psoriasis. J Invest Dermatol 133:1556–1564PubMedCrossRefGoogle Scholar
  31. 31.
    Deane JA, Fruman DA (2004) Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu Rev Immunol 22:563–598PubMedCrossRefGoogle Scholar
  32. 32.
    Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998) Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12:3499–3511PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Ding X, Bloch W, Iden S, Ruegg MA, Hall MN et al (2016) mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation. Nat Commun 7:13226PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10:262–267PubMedCrossRefGoogle Scholar
  35. 35.
    Eijkelenboom A, Burgering BM (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97PubMedCrossRefGoogle Scholar
  36. 36.
    Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619PubMedCrossRefGoogle Scholar
  37. 37.
    Essafi A, Gomes AR, Pomeranz KM, Zwolinska AK, Varshochi R et al (2009) Studying the subcellular localization and DNA-binding activity of FoxO transcription factors, downstream effectors of PI3K/Akt. Methods Mol Biol 462:201–211PubMedGoogle Scholar
  38. 38.
    Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5:671–688PubMedCrossRefGoogle Scholar
  39. 39.
    Florek AG, Wang CJ, Armstrong AW (2018) Treatment preferences and treatment satisfaction among psoriasis patients: a systematic review. Arch Dermatol Res 310:271–319PubMedCrossRefGoogle Scholar
  40. 40.
    Frigerio E, Colombo MD, Franchi C, Altomare A, Garutti C et al (2007) Severe psoriasis treated with a new macrolide: everolimus. Br J Dermatol 156:372–374PubMedCrossRefGoogle Scholar
  41. 41.
    Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC et al (2017) The PI3K pathway in human disease. Cell 170:605–635PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Fruman DA, Meyers RE, Cantley LC (1998) Phosphoinositide kinases. Annu Rev Biochem 67:481–507PubMedCrossRefGoogle Scholar
  43. 43.
    Gonzalez E, McGraw TE (2009) The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle 8:2502–2508PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24:7410–7425PubMedCrossRefGoogle Scholar
  45. 45.
    Guo S, Rena G, Cichy S, He X, Cohen P et al (1999) Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem 274:17184–17192PubMedCrossRefGoogle Scholar
  46. 46.
    Gupta D, Syed NA, Roesler WJ, Khandelwal RL (2004) Effect of overexpression and nuclear translocation of constitutively active PKB-alpha on cellular survival and proliferation in HepG2 cells. J Cell Biochem 93:513–525PubMedCrossRefGoogle Scholar
  47. 47.
    Gutknecht M, Schaarschmidt ML, Danner M, Otten M, Augustin M (2018) How to weight patient-relevant treatment goals for assessing treatment benefit in psoriasis: preference elicitation methods vs. rating scales. Arch Dermatol Res 310(8):1–11Google Scholar
  48. 48.
    Hambly R, Kirby B (2017) The relevance of serum vitamin D in psoriasis: a review. Arch Dermatol Res 309:499–517PubMedCrossRefGoogle Scholar
  49. 49.
    Hao JQ (2014) Targeting interleukin-22 in psoriasis. Inflammation 37:94–99PubMedCrossRefGoogle Scholar
  50. 50.
    Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988–1004PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Hong KK, Gwak MJ, Song J, Kim NI (2016) Nuclear factor-kappaB pathway activation and phosphatase and tensin homolog downregulation in psoriasis. Br J Dermatol 174:433–435PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Hresko RC, Murata H, Mueckler M (2003) Phosphoinositide-dependent kinase-2 is a distinct protein kinase enriched in a novel cytoskeletal fraction associated with adipocyte plasma membranes. J Biol Chem 278:21615–21622PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Huang L, Xue R (2014) The expressions of p-Akt and p-FoxO1 in the lesions of psoriasis vulgaris (in Chinese). Chin J Leprosy Skin Dis 30:737–739Google Scholar
  54. 54.
    Huang T, Lin X, Meng X, Lin M (2014) Phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin pathway in psoriasis pathogenesis. A potential therapeutic target? Acta Derm Venereol 94:371–379PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Imai-Sumida M, Chiyomaru T, Majid S, Saini S, Nip H et al (2017) Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways. Oncotarget 8:92032–92042PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P et al (2005) Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 171:1023–1034PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Jiang BH, Liu LZ (2009) PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 102:19–65PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kaestner KH, Knochel W, Martinez DE (2000) Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 14:142–146PubMedPubMedCentralGoogle Scholar
  59. 59.
    Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512PubMedCrossRefGoogle Scholar
  60. 60.
    Kops GJ, Burgering BM (2000) Forkhead transcription factors are targets of signalling by the proto-oncogene PKB (C-AKT). J Anat 197 Pt 4:571–574CrossRefGoogle Scholar
  61. 61.
    Kops GJ, Burgering BM (1999) Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling. J Mol Med (Berl) 77:656–665CrossRefGoogle Scholar
  62. 62.
    Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL et al (1999) Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398:630–634PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947CrossRefGoogle Scholar
  65. 65.
    Li Q, Huang H, He Z, Sun Y, Tang Y et al (2018) Regulatory effects of antitumor agent matrine on FOXO and PI3K-AKT pathway in castration-resistant prostate cancer cells. Sci China Life Sci 61:550–558PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Li Y, Man X, You L, Xiang Q, Li H et al (2014) Downregulation of PTEN expression in psoriatic lesions. Int J Dermatol 53:855–860PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett MB et al (2011) Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 187:490–500PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Liu Y, Luo W, Chen S (2011) Comparison of gene expression profiles reveals aberrant expression of FOXO1, Aurora A/B and EZH2 in lesional psoriatic skins. Mol Biol Rep 38:4219–4224PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Lizcano JM, Alessi DR (2002) The insulin signalling pathway. Curr Biol 12:R236–R238PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Lowes MA, Bowcock AM, Krueger JG (2007) Pathogenesis and therapy of psoriasis. Nature 445:866–873PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG (2013) The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol 34:174–181PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Ma J, Matkar S, He X, Hua X (2018) FOXO family in regulating cancer and metabolism. Semin Cancer Biol 50:32–41PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Madonna S, Scarponi C, Pallotta S, Cavani A, Albanesi C (2012) Anti-apoptotic effects of suppressor of cytokine signaling 3 and 1 in psoriasis. Cell Death Dis 3:e334PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Maehama T (2007) PTEN: its deregulation and tumorigenesis. Biol Pharm Bull 30:1624–1627PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378CrossRefGoogle Scholar
  76. 76.
    Malemud CJ (2009) The discovery of novel experimental therapies for inflammatory arthritis. Mediat Inflamm 2009: 698769Google Scholar
  77. 77.
    Malemud CJ (2015) The PI3K/Akt/PTEN/mTOR pathway: a fruitful target for inducing cell death in rheumatoid arthritis? Fut Med Chem 7:1137–1147CrossRefGoogle Scholar
  78. 78.
    Man X, Zhang X, Li H (2011) The Expression of Akt1,Akt2,Akt3 in the lesions of Psoriasis vulgaris the Chinese (in Chinese). J Dermatovenereol 25:338–340Google Scholar
  79. 79.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Manning BD, Toker A (2017) AKT/PKB Signaling: navigating the network. Cell 169:381–405PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Markman B, Dienstmann R, Tabernero J (2010) Targeting the PI3K/Akt/mTOR pathway–beyond rapalogs. Oncotarget 1:530–543PubMedPubMedCentralGoogle Scholar
  82. 82.
    Melnik BC (2013) Western diet-mediated mTORC1-signaling in Acne, psoriasis, atopic dermatitis, and related diseases of civilization: therapeutic role of plant-derived natural mTORC1 inhibitors. In: Watson R, Zibadi S (eds) Bioactive dietary factors and plant extracts in dermatology nutrition and health. Humana Press, Totowa, pp 397–419CrossRefGoogle Scholar
  83. 83.
    Mitra A, Raychaudhuri SK, Raychaudhuri SP (2012) Functional role of IL-22 in psoriatic arthritis. Arthritis Res Ther 14:R65PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Mitra A, Raychaudhuri SK, Raychaudhuri SP (2012) IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine 60:38–42PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Moeinifard M, Hassan ZM, Fallahian F, Hamzeloo-Moghadam M, Taghikhani M (2017) Britannin induces apoptosis through AKT-FOXO1 pathway in human pancreatic cancer cells. Biomed Pharmacother 94:1101–1110PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Monfrecola G, Lembo S, Caiazzo G, De Vita V, Di Caprio R et al (2016) Mechanistic target of rapamycin (mTOR) expression is increased in acne patients’ skin. Exp Dermatol 25:153–155PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Murayama K, Kimura T, Tarutani M, Tomooka M, Hayashi R et al (2007) Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors. Oncogene 26:4882–4888PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G et al (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98:10314–10319PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361:496–509PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Nograles KE, Davidovici B, Krueger JG (2010) New insights in the immunologic basis of psoriasis. Semin Cutan Med Surg 29:3–9PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    O’Shaughnessy RF, Welti JC, Cooke JC, Avilion AA, Monks B et al (2007) AKT-dependent HspB1 (Hsp27) activity in epidermal differentiation. J Biol Chem 282:17297–17305PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Ochaion A, Bar-Yehuda S, Cohen S, Barer F, Patoka R et al (2009) The anti-inflammatory target A(3) adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn’s disease. Cell Immunol 258:115–122PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L et al (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Pankow S, Bamberger C, Klippel A, Werner S (2006) Regulation of epidermal homeostasis and repair by phosphoinositide 3-kinase. J Cell Sci 119:4033–4046PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Paradis S, Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12:2488–2498PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Peng XD, Xu PZ, Chen ML, Hahn-Windgassen A, Skeen J et al (2003) Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev 17:1352–1365PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Pike MC, Lee CS, Elder JT, Voorhees JJ, Fisher GJ (1989) Increased phosphatidylinositol kinase activity in psoriatic epidermis. J Invest Dermatol 92:791–797PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Raychaudhuri SK, Raychaudhuri SP (2014) mTOR signaling cascade in psoriatic disease: double kinase mTOR inhibitor a novel therapeutic target. Indian J Dermatol 59:67–70PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Raychaudhuri SP, Raychaudhuri SK, Atkuri KR, Herzenberg LA, Herzenberg LA (2011) Nerve growth factor: a key local regulator in the pathogenesis of inflammatory arthritis. Arthritis Rheum 63:3243–3252PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Sa SM, Valdez PA, Wu J, Jung K, Zhong F et al (2007) The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol 178:2229–2240PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Saoncella S, Tassone B, Deklic E, Avolio F, Jon C et al (2014) Nuclear Akt2 opposes limbal keratinocyte stem cell self-renewal by repressing a FOXO-mTORC1 signaling pathway. Stem Cells 32:754–769CrossRefGoogle Scholar
  102. 102.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Saxena A, Raychaudhuri SK, Raychaudhuri SP (2011) Interleukin-17-induced proliferation of fibroblast-like synovial cells is mTOR dependent. Arthritis Rheum 63:1465–1466PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 169:361–371PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr (1998) Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA 95:7772–7777PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Shankar S, Chen Q, Srivastava RK (2008) Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO transcription factor. J Mol Signal 3:1–11CrossRefGoogle Scholar
  107. 107.
    Shi Q, Bao S, Maxwell JA, Reese ED, Friedman HS et al (2004) Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation. J Biol Chem 279:52200–52209PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Shirsath N, Mayer G, Singh TP, Wolf P (2015) 8-methoxypsoralen plus UVA (PUVA) therapy normalizes signalling of phosphorylated component of mTOR pathway in psoriatic skin of K5.hTGFbeta1 transgenic mice. Exp Dermatol 24:889–891PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Soares HP, Ming M, Mellon M, Young SH, Han L et al (2015) Dual PI3K/mTOR inhibitors induce rapid overactivation of the MEK/ERK Pathway in human pancreatic cancer cells through suppression of mTORC2. Mol Cancer Ther 14:1014–1023PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9:59–71PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H et al (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362CrossRefGoogle Scholar
  112. 112.
    Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB et al (1997) Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277:567–570PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Tzivion G, Dobson M, Ramakrishnan G (2011) FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta 1813:1938–1945PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    van der Vos KE, Coffer PJ (2008) FOXO-binding partners: it takes two to tango. Oncogene 27:2289–2299PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R et al (2012) Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. Nat Cell Biol 14:829–837PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Wang H, Ran LW, Hui K, Wang XY, Zheng Y (2017) Expressions of survivin, PI3K and AKT in keratinocytes in skin lesions and their pathogenic role in psoriasis vulgaris. Nan Fang Yi Ke Da Xue Xue Bao 37:1512–1516PubMedPubMedCentralGoogle Scholar
  117. 117.
    Wang Z, Yu T, Huang P (2016) Post-translational modifications of FOXO family proteins (review). Mol Med Rep 14:4931–4941PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S et al (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428:332–337PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Yao R, Cooper GM (1995) Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267:2003–2006PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Yuan TL, Wulf G, Burga L, Cantley LC (2011) Cell-to-cell variability in PI3K protein level regulates PI3K-AKT pathway activity in cell populations. Curr Biol 21:173–183PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Zhang X, Liu H, Ma S (1999) Up-regulation of phosphatidylinositol 3-kinase in psoriatic lesions. Chin Med J (Engl) 112:1097–1100Google Scholar
  122. 122.
    Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813:1978–1986PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Zhang X, Zhou P, You L (2009) Increased activities of Akt in psoriatic epidermis (in Chinese). Chin J Dermatol 42:413–416Google Scholar
  124. 124.
    Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Graduate SchoolBeijing University of Chinese MedicineBeijingChina
  2. 2.Department of DermatologyChina-Japan Friendship HospitalBeijingChina

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