PI3K/AKT/mTOR pathway

mTOR signaling pathway.

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane.[1] AKT can have a number of downstream effects such as activating CREB,[2] inhibiting p27,[3] localizing FOXO in the cytoplasm,[3] activating PtdIns-3ps,[4] and activating mTOR[3] which can affect transcription of p70 or 4EBP1.[3] There are many known factors that enhance the PI3K/AKT pathway including EGF,[5] shh,[2] IGF-1,[2] insulin,[3] and calmodulin.[4] Both leptin and insulin recruit PI3K signalling for metabolic regulation.[6] The pathway is antagonized by various factors including PTEN,[7] GSK3B,[2] and HB9.[5]

In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. This pathway is necessary, however, to promote growth and proliferation over differentiation of adult stem cells, neural stem cells specifically.[2] It is the difficulty in finding an appropriate amount of proliferation versus differentiation that researchers are trying to determine in order to utilize this balance in the development of various therapies.[2] Additionally, this pathway has been found to be a necessary component in neural long term potentiation.[4][8]

  1. ^ King D, Yeomanson D, Bryant HE (May 2015). "PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma". Journal of Pediatric Hematology/Oncology. 37 (4): 245–51. doi:10.1097/MPH.0000000000000329. PMID 25811750. S2CID 42323379.
  2. ^ a b c d e f Peltier J, O'Neill A, Schaffer DV (September 2007). "PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation". Developmental Neurobiology. 67 (10): 1348–61. doi:10.1002/dneu.20506. PMID 17638387. S2CID 16337839.
  3. ^ a b c d e Cite error: The named reference Rafalski_2011 was invoked but never defined (see the help page).
  4. ^ a b c Cite error: The named reference Man_2003 was invoked but never defined (see the help page).
  5. ^ a b Ojeda L, Gao J, Hooten KG, Wang E, Thonhoff JR, Dunn TJ, et al. (2011). "Critical role of PI3K/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF". PLOS ONE. 6 (8): e23414. Bibcode:2011PLoSO...623414O. doi:10.1371/journal.pone.0023414. PMC 3160859. PMID 21887250.
  6. ^ Garcia-Galiano D, Borges BC, Allen SJ, Elias CF (2019). "PI3K signalling in leptin receptor cells: Role in growth and reproduction". Journal of Neuroendocrinology. 31 (5): e12685. doi:10.1111/jne.12685. PMC 6533139. PMID 30618188.
  7. ^ Wyatt LA, Filbin MT, Keirstead HS (August 2014). "PTEN inhibition enhances neurite outgrowth in human embryonic stem cell-derived neuronal progenitor cells". The Journal of Comparative Neurology. 522 (12): 2741–55. doi:10.1002/cne.23580. PMID 24610700. S2CID 205683500.
  8. ^ Sui L, Wang J, Li BM (October 2008). "Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex". Learning & Memory. 15 (10): 762–76. doi:10.1101/lm.1067808. PMID 18832563.