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Find antibodies, assays, and proteins associated with the Akt pathway, powered by Linnea™ Guide to Genes.

  • AKT Pathway Overview

    The serine/threonine protein kinase Akt, also known as protein kinase B (PKB) or RAC-PK, was initially identified as one of the downstream targets of phosphatidylinositol-3 kinase (PI3K). Currently, Akt is one of the most actively studied kinases or kinase pathways in both the basic research and drug development arenas.

    Activated Akt plays a key role in mediating signals for cell growth, cell survival (anti-apoptotic), cell-cycle progression, differentiation, transcription, translation, and glucose metabolism.1 Recent advances in Akt signaling have focused on understanding even more cellular processes and identifying cellular substrates that are physiologically relevant in vivo. These efforts have uncovered important roles for Akt regulation in the G2/M transition of the cell cycle,2 breast and prostate cancer tumorigenesis,3 modulation of neuronal synapse activity,4neurodegeneration,5 and insulin resistance–induced diabetes.6

AKT Isoforms

Akt comprises three highly conserved isoforms in mammals, designated Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ. Although each isoform is expressed differentially in a tissue-specific manner, they all contain an N-terminal pleckstrin homology (PH) domain, which mediates lipid–protein or protein–protein interactions, a kinase domain, and a C-terminal regulatory domain. Akt is activated by a diverse array of growth factors, cytokines, and other physiologic stimuli in a PI3K-dependent manner through a multistep process involving both membrane translocation and phosphorylation. Binding of the p85 subunit of PI3K to certain tyrosine phosphorylation sites within the cytoplasmic domain of many receptor tyrosine kinases, and soluble tyrosine kinases, such as FAK and Pyk2, specifically targets recruitment and activation of this lipid kinase. Activated PI3K generates phosphatidylinositol (3,4,5) trisphosphate (PtdIns (3,4,5)P3), which in turn recruits inactive Akt/PKB from the cytosol to the plasma membrane. Here Akt undergoes a large conformational change, making it accessible to phosphorylation at threonine 308 in the activation loop of the kinase domain by phosphoinositide-dependent protein kinase-1 (PDK-1). PDK-1 is an enzyme that phosphorylates many different kinases at their corresponding activation loop site, thereby serving as a central modulator of multiple kinase pathways. Phosphorylation within the activation loop allows subsequent phosphorylation at serine 473 in the hydrophobic regulatory domain. This phosphorylation event remained a mystery for many years;however, roles for autophosphorylation, PDK2, mammalian target of rapamycin (mTOR), and more recently, DNA-PK, have been reported.7,8 Once phosphorylated at serine 473, Akt remains active even if the threonine 308 site becomes dephosphorylated.

AKT Activation

Activation of Akt results in phosphorylation of a wide range of protein substrates including adaptor proteins (Bcl-2, BAD, MDM2, PRAS40), other kinases (glycogen synthase kinase-3 [GSK-3], IκB kinase-β [IKK-β], mTOR), GTPases (Rac/cdc42, Rho), caspases (CASP9), metabolic enzymes (endothelial nitric oxide synthase [eNOS], 6-phosphofructo-2-kinase), cell cycle regulators (MDM2, p21Cip1, p27Kip1), transcription factors (FOXO/Forkhead), and cancer susceptibility genes (BRCA1). Differential regulation of Akt substrates and different subcellular locations of these phosphorylated substrates play an important role in directing the different phenotypic outcomes.

Substrates

AS160 and PRAS40 are two recently identified substrates that are being intensely studied. AS160 is found associated with GLUT4 vesicles, and phosphorylation at threonine 642 by Akt promotes GLUT4 transport to the plasma membrane, allowing increased glucose uptake.9 PRAS40 phosphorylation at threonine 246 is induced by many stimuli, and this is required for both its metabolic and survival/anti-apoptotic signaling roles. Indeed, reduced PRAS40 phosphorylation has been associated with insulin resistance in insulin-responsive tissues10 and with increased sensitivity to chemotherapeutic intervention of malignant melanoma.11 Interestingly, PRAS40 has recently been shown to bind to mTOR and inhibit its signaling and is itself a substrate of the mTOR kinase.12–14 Therefore, in response to insulin, mTOR and Akt play opposing roles, where PRAS40 is a critical mediator of these events.

References

  1. Brazil, D.P. et al. (2004) TIBS 29:233–242. 
  2. Shtivelman, E. et al. (2002) Curr Biol 12:919–924.
  3. Li, L. et al. (2003) Mol Cell Biol 23:9389–9404.
  4. Wang, Q. et al. (2003) Neuron 38:915–928.
  5. Chen, H.K. et al. (2003) Cell 113:457–468.
  6. Cho, H. et al. (2001) Science 292:1728–1731.
  7. Hresko, R.C. and Mueckler, M. (2005) J Biol Chem 280:40406–40416.
  8. Lu, D. et al. (2006) J Biol Chem 281:22799–22807.
  9. Bertola, A. et al. (2007) J Biol Chem 282:10325–10332.
  10. Nascimento, E.B. et al. (2006) Diabetes 55:3221–3228.
  11. Madhunapantula, S.V. et al. (2007) Cancer Res 67:3626–3636.
  12. Oshiro, N. et al. (2007) J Biol Chem 282:20329–20339.
  13. Vander Haar, E. et al. (2007) Nat Cell Biol 9:316–323.
  14. Sancak, Y. et al. (2007) Mol Cell 25:903–915.