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Resource Center
Cell Signaling
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Akt/Pkb Signaling Pathway
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Ampk Signaling Pathway
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Camp-Dependent Pathway
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Eph/Ephrin Signaling Pathway
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Hedgehog Signaling Pathway
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Hippo Signaling Pathway
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Insulin Signal Transduction Pathway
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Jak-Stat Signaling Pathway
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Wnt Signaling Pathway
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Mapk/Erk Signaling Pathway
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Tlr Signaling Pathway
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Tgf Beta Signaling Pathway
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Pi3K/Akt/Mtor Signaling Pathway
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EGFR Signaling Pathway
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Notch Signaling Pathway
PI3K/AKT/mTOR Signaling Pathway
PI3K (Phosphatidylinositol 3-kinase)
PI3K, also known as phosphatidylinositol 3-kinases (PI3Ks), is a type of cell signaling enzyme that participates in cellular functions such as growth, proliferation, differentiation, and transport. The PI3K family is divided into classes I, II, III, and IV. PI3K phosphorylates membrane phosphoinositide PIP2 (phosphatidylinositol-4,5-diphosphate) in vivo to produce PIP3 (phosphatidylinositol-3,4,5-triphosphate), which is an important second messenger that activates downstream signaling.
AKT (protein kinase B)
AKT， Also known as protein kinase B (PKB), it is a collective term for three serine/threonine specific protein kinases that play critical roles in various cellular processes such as cell proliferation, apoptosis, and transcription. There are three different gene encoded isoforms of protein kinase B. These three genes are called AKT1, AKT2, and AKT3
AKT1: it can prevent cell apoptosis, promote protein synthesis, and increase cell survival rate.
AKT2: It is an essential substance in the glucose transport process and can also promote cell migration
AKT3: The mechanism is currently unclear, but research suggests that it may be related to brain activity.
AKT is recruited to the plasma membrane through PIP3, where it is phosphorylated (via PDK1 and mTORC2) and activated. Once activated, AKT phosphorylates substrates involved in promoting cell survival, growth, proliferation, and metabolism. Some key objectives include:
BAD: Inhibiting cell apoptosis by inactivating this pro apoptotic protein.
GSK-3 β: Promotes cell survival by inhibiting glycogen synthase kinase, otherwise glycogen synthase kinase would promote cell apoptosis.
FOXO transcription factors: AKT phosphorylation and FOXO inactivation can reduce the expression of pro apoptotic genes.
mTOR
mTOR: Mammalian target protein of rapamycin (mTOR), also known as the mechanistic target protein of rapamycin and sometimes referred to as FK506 binding protein 12 rapamycin related protein 1 (FRAP1), is a kinase encoded by the human mTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase related kinase family in protein kinases.
mTOR plays an important role in regulating cell growth, proliferation, division, apoptosis, and autophagy in the process of cell signal transduction. As a result, there are many signaling pathways in which mTOR is the main effector.
mTOR is a serine/threonine kinase that exists in two complexes: mTORC1 and mTORC2.
mTORC1: Activated by AKT, this complex promotes protein synthesis, lipid synthesis, and inhibits autophagy by activating downstream effectors that regulate protein translation, such as S6K and 4E-BP1.
mTORC2: participates in the regulation of the cytoskeleton and also contributes to the complete activation of AKT.
mTORC1 is regulated by nutrients, energy status (via AMPK), and growth factors.
Introduction of PI3K/AKT/mTOR signaling pathway
The PI3K/AKT/mTOR signaling pathway is a signaling pathway related to cell proliferation, carcinogenesis, and other cell cycles. It plays an important role in regulating the cell cycle. Firstly, P13K is activated, and the activation signal of P13K phosphorylates and activates AKT. AKT produces downstream responses that activate mTOR and affect the transcription of p70 or 4EBP1. Many factors can enhance or inhibit the PI3K/AKT pathway, such as enhanced factors including EGF, IGF-1, insulin, and calmodulin. Factors that weaken or inhibit include PTEN, GSK3B, etc.
Fig3: Overview of signal transduction pathways involved in apoptosis. (Figure Source:Wikipedia)
Cancer in PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is a central regulatory factor in ovarian cancer.
Common genomic abnormalities in breast cancer are related to PI3K/AKT/mTOR pathway abnormalities.
PI3Kb is mainly involved in the activation of platelets and thrombotic diseases, which contributes to tumor proliferation. Interfering with PI3Kb gene may be a method to treat certain types of bladder cancer.
The PI3K pathway is the main source of drug resistance in prostate cancer.
Application to PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is essential for promoting the growth and proliferation of adult stem cells, especially neural stem cells, rather than differentiation. The PI3K-AKT signaling pathway also plays an important role in brain growth, and when the PI3K signal is disrupted, brain growth changes. This pathway promotes tumor cell proliferation and can be treated by developing cytokine inhibitors such as PI3K inhibitors, Akt inhibitors, mTOR inhibitors, PTEN inhibitors, or dual inhibitors such as PI3K/AKT/mTOR dual inhibitors.
Reference
[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] 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.
[3] https://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway