PIP3/AKT pathway

General description

PIP3/AKT pathway is a shared down-stream pathway by a variety of upstream signalling events initiated by EGFR, NGFR, and insulin receptors. The activation of PI3-kinase, by different growth factors, insulin, IGF-1 (insulin-like growth factor-1), certain cytokins (e.g. IL2) and environmental and cellular stresses, facilitates the production of PIP3, which in turn recruits AKT to the membrane. The full activation of AKT requires phosphorylation at Thr-308 by PDK-1( phosphoinositide-dependent kinase-1) and phosphorylation at Ser-473 primarily via mTORC2 (mammalian targert of rapamycin-2). Activated AKT can exert positive effect on mTOR, however inactivates GSK3Beta and FOXO.

PIP3/AKT pathway is related to normal ageing, with studies showing that reduces activity of PIP3/AKT increases the lifespan (Kenyon, 2010)⁠. Therefore, Many negative regulator of this pathway, including PTEN, PP2A, mTORC1, adjusting the activation PIP3/AKT, and plays a crucial role on longevity.

References:
  • Kenyon, C. J. (2010). The genetics of ageing. Nature, 464, 504–512. doi:10.1038/nature09047
Reactome REACT_75829.5
KEGG pathway
04151
Involvement in Alzheimer's disease

Insulin resistance has been found in significant number of neurons from AD patients' brains, which was a result from the sustained activation of neuronal PIP3/AKT, and the negative feed back from mTOR to IRS-1, therefore dis-coupling PIP3/AKT pathway from insulin receptor activation (M. de la Monte, 2012; O’Neill, Kiely, Coakley, Manning, & Long‑Smith, 2012)⁠⁠⁠.

Furthermore, mTOR can also increase the translation of both Tau and APP, contributing to impaired glutamatergic synaptic transmission (Morita & Sobue, 2009; Westmark & Malter, 2007)⁠.

References:
  • M. de la Monte, S. (2012). Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer’s Disease. Current Alzheimer Research. doi:10.2174/156720512799015037
  • Morita, T., & Sobue, K. (2009). Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. The Journal of Biological Chemistry, 284, 27734–27745. doi:10.1074/jbc.M109.008177
  • O’Neill, C., Kiely, A. P., Coakley, M. F., Manning, S., & Long‑Smith, C. M. (2012). Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer’s disease. Biochemical Society Transactions. doi:10.1042/BST20120080
  • Westmark, C. J., & Malter, J. S. (2007). FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biology, 5, 0629–0639. doi:10.1371/journal.pbio.0050052
Proteins involved
MTOR MTOR_HUMAN
GSK3B GSK3B_HUMAN
AKT1 AKT1_HUMAN
PIK3CA PK3CA_HUMAN
FYN FYN_HUMAN