Phosphatidylinositol 3-kinase–Akt signaling pathway proteins (PI3K/Akt pathway)

The Phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway proteins constitute a central intracellular signaling axis that regulates essential cellular processes including growth, proliferation, survival, and metabolism [6, 12]. This pathway is typically activated by the binding of extracellular ligands to receptor tyrosine kinases (RTKs) or G-protein coupled receptors (GPCRs), which recruit and activate class I PI3Ks at the plasma membrane [13]. Activated PI3K converts the membrane lipid PIP2 to PIP3, which serves as a docking site for the serine/threonine kinase Akt, facilitating its activation by upstream kinases like PDK1 and mTORC2 [12, 15]. Once active, Akt phosphorylates a vast array of downstream substrates to promote cell survival and inhibit apoptosis [6, 14]. Aberrant activation of this pathway, primarily through PIK3CA mutations, AKT1 mutations, or loss of the negative regulator PTEN, is a hallmark of many human cancers, including breast, prostate, and hematological malignancies [16, 19]. Consequently, this pathway is a major therapeutic target, with several approved drugs such as the PI3K-alpha inhibitor alpelisib and the pan-Akt inhibitor capivasertib designed to block specific nodes of the cascade [14, 19]. Clinical challenges include managing on-target toxicities such as hyperglycemia and immune-mediated adverse events like pneumonitis [1, 5].

Other names

PI3K-Akt signaling axisPI3K/Akt/mTOR pathwayPhosphoinositide 3-kinase–protein kinase B signalingPI3K/PKB pathway

Phosphatidylinositol 3-kinase inhibition (isoform-specific or pan-class I), Akt (Protein kinase B) inhibition, and mTOR (mammalian target of rapamycin) inhibition to block downstream pro-survival and proliferative signaling.