Signal transduction - AKT signaling

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AKT signaling

RAC-alpha serine/threonine kinases (AKTs) are crucial mediators of various cellular process, such as apoptosis, regulation of cell cycle, protein synthesis and regulation of metabolism. The activity of AKT is modulated by various proteins, including Phosphatidylinositol-3-kinase (PI3K), Phosphoinositide-dependent kinase 1 (PDK), phosphotases PTEN, PP2A, and heat-shock protein (Hsp90).

PI3K converts phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), which is secondary messenger involved the in regulation of various process [1]. PI(3,4,5)P3 associates with the inner lipid bilayer of the plasma membrane and promotesthe recruitment of proteins with pleckstrin homology (PH) domains such as AKT and PDK. Upon binding to the membrane AKT and PDK became active. Notably, translocation of AKT to the plasma membrane also facilitates its phosphorylation by PDK [2].

AKT activity can be inhibited indirectly though the t phosphatase PTEN that cleaves the 3' phosphate from PI(3,4,5)P3 to generate PI(4,5)P2. PTEN therefore, acts to decrease levels of PI(3,4,5)P3 causing an antagonistic effect of AKT-inducedcell survival [3].

The phosphatase PP2A dephosphorylates and inhibits AKT directly and this is counteracted by Hsp90. Hsp90 forms a complex with AKT and prevents PP2A-mediated dephosphorylation. Hsp90 plays an important role in maintaining AKT kinase activity [4].

Activated AKT prevents cells from undergoing apoptosis by inhibiting proapoptotic proteins BCL2-associated agonist of cell death (BAD) and Caspase-9 [5]. AKT induces phosphorylation of BAD, preventing BAD from binding with anti-apoptotic factor BCL2-like 1 (BCL-X) therby reducing antiapoptotic events [6].

AKT can interfere with cell death via a member of the forkhead family of transcription factors (e.g., Forkhead box O3 (FOXO3A), which is a direct target for phosphorylation by AKT). FOXO3A has been implicated in the expression of the FAS ligand (FasL) and the Bcl-2 interacting mediator of cell death (Bim), which can induce cell death. Upon phosphorylation by AKT, FOXO3A is retained in the cytosol preventing transcriptional regulation and expression of FasL and Bim in the nuclease, allowing the cell survival [7].

AKT also regulates the activity of other transcription factors, such as nuclear factor-kappaB (NF-kB), Tumor protein p53 (p53), c-Myc. AKT phosphorilates and activates I-kB kinase (IKK), that regulate the activity of the NF-kB transcription factor. When bound to its cytosolic inhibitor I-kB, NF-kB is inactive. Upon phosphorylation of I-kB by IKK, the inhibitor is degraded, allowing NF-kB to move to the nucleus and activate the transcription of antiapoptotic proteins [8].

AKT phosphorylates ubiquitin-protein ligase E3 Mdm2 p53 binding protein homolog (MDM2) that results in its translocation into the nucleus where it binds to transcription factor p53. p53 mediates apoptosis through transactivation of apoptotic activator BAX [9]. MDM2 interacts with the p53, inhibits its transcriptional activity and targets it for degradation by the proteasome [10].

AKT affects the cell cycle progression by regulating the Cyclin D function. This is accomplished by phosphorylation of Cyclin-dependent kinase inhibitor 1A (p21/WAF1) by AKT. This result to cytoplasmic localization of p21/WAF1, thereby preventing its function in the nucleus. In the nucleous, the protein p21/WAF1 interacts with and inhibits the essential DNA replication factor, proliferating-cell nuclear antigen (PCNA). p21/WAF1 and PCNA forms complex with Cyclin D [11].

Another target for AKT is Glycogen synthase kinase 3 (GSK3), which negativly regulates glycogen synthesis and cell cycle progression via inhibitory phosphorylation of glycogen synthase and transcription factors c-Myc and Cyclin D, respectively.

Additionally, FOXO3A has been implicated in expression of the Cyclin-dependent kinase inhibitor 1B (P27KIP1), which binds with and inhibits Cyclin D [12].

The activation of AKT results in the stimulation of protein synthesis via activation of Ribosomal protein S6 kinase (p70S6K). The activation of p70S6K by AKT occurs via direct and indirect mechanisms. The indirect process is mediated by FKBP-rapamycin associated protein (FRAP1). In absence of AKT-mediated phosphorylation, Tuberin via the small GTPase Rheb inhibits FRAP1, allowing the activation of P70S6K the leads to multiple phosphorylation events of 40S ribosomal protein S6 (RPS6) to trigger protein synthesis [13].

References:

  1. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  2. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  3. Downward J
    PI 3-kinase, Akt and cell survival. Seminars in cell & developmental biology 2004 Apr;15(2):177-82
  4. Sato S, Fujita N, Tsuruo T
    Modulation of Akt kinase activity by binding to Hsp90. Proceedings of the National Academy of Sciences of the United States of America 2000 Sep 26;97(20):10832-7
  5. Tsugawa K, Jones MK, Sugimachi K, Sarfeh IJ, Tarnawski AS
    Biological role of phosphatase PTEN in cancer and tissue injury healing. Frontiers in bioscience : a journal and virtual library 2002 May 1;7:e245-51
  6. Datta SR, Ranger AM, Lin MZ, Sturgill JF, Ma YC, Cowan CW, Dikkes P, Korsmeyer SJ, Greenberg ME
    Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Developmental cell 2002 Nov;3(5):631-43
  7. Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR, Silver PA
    A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer cell 2003 Dec;4(6):463-76
  8. Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G, Sizemore N
    The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene 2005 Feb 3;24(6):1021-31
  9. Shen Y, White E
    p53-dependent apoptosis pathways. Advances in cancer research 2001;82:55-84
  10. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M
    Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 2002 Feb 14;21(8):1299-303
  11. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC
    Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature cell biology 2001 Mar;3(3):245-52
  12. Liang J, Slingerland JM
    Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell cycle (Georgetown, Tex.) 2003 Jul-Aug;2(4):339-45
  13. Panwalkar A, Verstovsek S, Giles FJ
    Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer 2004 Feb 15;100(4):657-66

  1. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  2. Brader S, Eccles SA
    Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004 Jan-Feb;90(1):2-8
  3. Downward J
    PI 3-kinase, Akt and cell survival. Seminars in cell & developmental biology 2004 Apr;15(2):177-82
  4. Sato S, Fujita N, Tsuruo T
    Modulation of Akt kinase activity by binding to Hsp90. Proceedings of the National Academy of Sciences of the United States of America 2000 Sep 26;97(20):10832-7
  5. Tsugawa K, Jones MK, Sugimachi K, Sarfeh IJ, Tarnawski AS
    Biological role of phosphatase PTEN in cancer and tissue injury healing. Frontiers in bioscience : a journal and virtual library 2002 May 1;7:e245-51
  6. Datta SR, Ranger AM, Lin MZ, Sturgill JF, Ma YC, Cowan CW, Dikkes P, Korsmeyer SJ, Greenberg ME
    Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Developmental cell 2002 Nov;3(5):631-43
  7. Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR, Silver PA
    A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer cell 2003 Dec;4(6):463-76
  8. Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G, Sizemore N
    The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene 2005 Feb 3;24(6):1021-31
  9. Shen Y, White E
    p53-dependent apoptosis pathways. Advances in cancer research 2001;82:55-84
  10. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M
    Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 2002 Feb 14;21(8):1299-303
  11. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC
    Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature cell biology 2001 Mar;3(3):245-52
  12. Liang J, Slingerland JM
    Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell cycle (Georgetown, Tex.) 2003 Jul-Aug;2(4):339-45
  13. Panwalkar A, Verstovsek S, Giles FJ
    Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer 2004 Feb 15;100(4):657-66

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