page_title: Akt/PKB signaling pathway
section_title: Cell cycle progression
hierarchical_section_title: Akt/PKB signaling pathway / Downstream effects / Cell cycle progression
caption_attribution_description: English: Akt (Protein Kinase B) substrates involved in cell cycle progression. Akt promotes increase in Cyclin D1 transcription and translation, and the export of cyclin-dependent kinase inhibitors p21 and p27.
context_page_description: The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.
  Initial stimulation by one of the growth factors causes activation of a cell surface receptor and phosphorylation of PI3K. Activated PI3K then phosphorylates lipids on the plasma membrane, forming second messenger phosphatidylinositol-trisphosphate. Akt, a serine/threonine kinase, is recruited to the membrane by interaction with these phosphoinositide docking sites, so that it can be fully activated.
  Activated Akt mediates downstream responses, including cell survival, growth, proliferation, cell migration and angiogenesis, by phosphorylating a range of intracellular proteins. The pathway is present in all cells of higher eukaryotes and is highly conserved.
  The pathway is highly regulated by multiple mechanisms, often involving cross-talk with other signaling pathways. Problems with PI3K-Akt pathway regulation can lead to an increase in signaling activity. This has been linked to a range of diseases such as cancer and type 2 diabetes.
context_section_description: Akt promotes G1-S phase cell cycle progression by phosphorylating and inactivating glycogen synthase kinase 3 (GSK-3) at Ser9. This prevents the phosphorylation and degradation of cyclin D1.
  
  Therefore, Akt promotes G1 phase progression in a positive feedback loop. Akt promotes cyclin D1 translation via indirect activation of mTOR. mTOR increases translation of cyclin D1 by activating ribosomal protein S6K, and inhibiting eukaryotic translation initiation factor 4E-binding protein (4E-BP), thus increasing eIF4e activity.
  Akt both indirectly and directly regulates cyclin-dependent kinase (CDK) inhibitors p21Cip1 and p27ᴷⁱᵖ¹ , allowing cell cycle progression. Akt phosphorylates p27ᵏⁱᵖ¹ at Thr157, preventing its nuclear import. In addition, Akt phosphorylates Thr145 and Ser146 of p21Cip1, preventing PCNA binding and decreasing stability. Akt phosphorylation of Foxo transcription factors also affects the cell cycle, as inhibitory phosphorylation of FoxO4 (also named AFX) prevents p27 gene expression.
caption: The effects of Akt activation on Cell Cycle progression
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