Akt/PKB signaling pathway
PI3 Kinase is a lipid kinase that is activated (via an SH2-domain adaptor) by signals (e.g., members of the insulin-like growth factor (IGF) family of signal proteins) transmitted by many transmembrane receptors with protein kinase cytosolic domains. This activation leads to production from membrane inositol of the inositol phospholipids PtdIns(3,4,5)P3 and PtdIns(3,4)P2.
[PI(4,5)P2 to PI(3,4,5)P3 & PI(4)P to PI(3,4)P2]
These in turn signal to a constitutive membrane threonine kinase called PDK-1 and, simultaneously, to a cytosolic protein kinase called Akt (or alternatively Protein Kinase B, PKB).
Interaction between the inositol phospholipids and Akt, together with activation of PDK-1 recruits Akt into a complex with PDK-1 on the inner leaflet of the cell membrane. (PIP3 recruits PDK-1 and Akt to the plasma membrane. PDK-1 phosphorylates and thus activates Akt.) This complex phosphorylates many highly significant substrates. Akt indirectly activates (not phosphorylates) mTOR, which lies at the heart of growth regulatory pathways.
mTOR promotes cell growth by:
- activating S6kinase (an activator of translation)
- activating PKC (so turning on many synthetic and secretory pathways)
- inhibiting p21 (so releasing cells from G1 arrest)
- inhibiting GSK3β (with similar effect, since GSK3β targets cyclin D for proteolysis)
Akt also phosphorylates Bad (a pro-apoptotic protein,which in its non-phosphorylated state, promotes apoptosis) which sequesters it and keeps it out of action, promoting cell survival.
The activity of this powerful, branching signaling pathway can be turned down close to source, however, through removal of the phosphate groups from the inositol phospholipids by the 3’ phosphoinositide phosphatase PTEN. Deficiency of PTEN therefore facilitates inappropriate entry to the cell cycle, through generation of prolonged inositol phospholipid signals after growth factor stimulation. Many tumor cells completely lack PTEN activity. PTEN is therefore a tumor suppressor gene.
- Song G, Ouyang G, Bao S (2005). "The activation of Akt/PKB signaling pathway and cell survival". J. Cell. Mol. Med. 9 (1): 59–71. doi:10.1111/j.1582-4934.2005.tb00337.x. PMID 15784165.
- DeFeo-Jones D, Barnett SF, Fu S, et al. (February 2005). "Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members". Mol. Cancer Ther. 4 (2): 271–9. PMID 15713898.
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