page_title: Akt/PKB signaling pathway
section_title: Cell survival and apoptosis
hierarchical_section_title: Akt/PKB signaling pathway / Downstream effects / Cell survival and apoptosis
caption_attribution_description: The downstream effects of Akt (Protein Kinase B) on cell survival and apoptosis. Phosphorylation of some substrates decreases their activity (inhibitory phosphorylation), whilst phosphorylation of other substrates increases their activity (stimulatory phosphorylation).
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: The Akt-PI3K pathway is essential for cell survival as activated Akt influences many factors involved in apoptosis, either by transcription regulation or direct phosphorylation.
   In the nucleus, Akt inhibits transcription factors that promote the expression of cell death genes, and enhances transcription of anti-apoptotic genes. A well studied example is the Forkhead family transcription factors (FoxO/FH), of which FKHR/FoxO1, FKHRL1/FoxO3 and AFX/FoxO4 are directly phosphorylated by Akt.
  This phosphorylation induces export to the cytosol where they are sequestered by 14-3-3 proteins and eventually undergo degradation via the ubiquitin-proteasome pathway.
  Akt also positively regulates some transcription factors to allow expression of pro-survival genes. Akt can phosphorylate and activate the IκB kinase IKKα, causing degradation of IκB and nuclear translocation of NF-κB where it promotes expression of caspase inhibitors, c-Myb and Bcl-xL. Also promoting cell survival, cAMP response element binding protein (CREB) is phosphorylated by Akt at Ser133, stimulating recruitment of CREB-binding protein (CBP) to the promoter of target genes, such as Bcl-2. Akt has also been shown to phosphorylate murine double minute 2 (Mdm2), a key regulator of DNA damage responses, at Ser166 and Ser186. Phosphorylation of Mdm2 by Akt upregulates its ubiquitin-ligase activity, therefore indirectly suppressing p53-mediated apoptosis. Another target of Akt is the Yes-associated protein (YAP), phosphorylated at Ser127 leading to 14-3-3 binding and cytosolic localisation. Therefore, it cannot co-activate p73-mediated apoptosis in response to DNA damage.
  Akt negatively regulates pro-apoptotic proteins by direct phosphorylation. For example, phosphorylation of BAD, the Bcl-2 family member, on Ser136 causes translocation from the mitochondrial membrane to the cytosol, where it is sequestered by 14-3-3 proteins. Akt phosphorylates Caspase-9 on Ser196, preventing a caspase cascade leading to cell death. Akt also phosphorylates MAP kinase kinase kinases (MAPKKK) upstream of the stress-activated protein kinase (SAPK) pathway. Phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) on Ser83 and mixed lineage kinase 3 (MLK3) on Ser674 inhibits their activity and prevents MAP kinase induced apoptosis.
caption: The substrates of Akt involved in promoting cell survival or blocking apoptosis
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