Phosphatidylinositol 3kinase PI3KAKT pathway A brief overview

Evidence has largely supported the phosphatidylinositol 3-kinase (PI3K)-AKT signalling pathway as a key regulatory system essential to mammalian cell proliferation, survival, and metabolism. The gain- or loss-of-function of components of this pathway lead to neoplastic transformation in a wide spectrum of human cancers, including CaP. Briefly, the canonical PI3K/AKT pathway is activated by mitogenic growth factor stimulation of receptor tyrosine kinases (RTKs), the most common RTKs include Epidermal Growth Factor Receptor (EGFR, ERBB1), Her2 (EGFR-2, ERBB2), KIT, PDGFRa, and MET. Receptor activation causes RTKs to dimerize and undergo autophosphorylation at tyrosine residues and enables interaction with Src Homology 2 (SH2) domain-containing molecules. The signal then becomes transduced, through the oncogene, RAS, and ultimately leads to the conversion of membrane phosphati-dylinositol-bis-phosphate (PI(3,4)P2; PIP2) to phosphatidylinositol-tri-phosphate (PI(3,4,5)P3; PIP3) by PI3K. The presence of PIP3 mediates the recruitment of AKT (also known as PKB) to the plasma membrane and its subsequent phosphorylation by 3-Phosphoinositide- Dependent protein Kinase (PDK) 1 and PDK 2 at Threonine 308 (T308) and Serine 473 (S473), respectively. Activated AKT or phosphorylated AKT (P-AKT) is the central effector of many downstream signaling pathways regulating protein synthesis, cell cycle, cell death, cell growth, and cell survival [summarized in Reference 82]. The loss and/or mutation of the tumor suppressor protein and negative regulator of the PI3K/AKT pathway, Phosphatase and Tensin homolog deleted on chromosome TEN (PTEN), is a common event in various cancers, causing the constitutive activation of PI3K/Akt signalling. PTEN, a dual protein and lipid phosphatase, dephosphorylates PIP3 to PIP2, hence, buffering the proliferative and transformative effects of the PI3K. This review will primarily focus on the most studied canonical PI3K/AKT pathway.

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