PI3KAKTpolku

PI3KAktpolku, also known as the PI3K-Akt pathway or the PI3K/AKT/mTOR pathway, is a major signal transduction cascade that promotes cell growth, survival, and metabolism in response to extracellular cues. Activation typically begins when growth factors bind receptor tyrosine kinases (RTKs) or other receptors, leading to the recruitment and activation of class I PI3K at the cell membrane.

Class I PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 serves as a docking site for pleckstrin homology (PH) domain-containing proteins, notably Akt and PDK1. Akt is then activated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTOR complex 2 (mTORC2).

Active Akt phosphorylates many substrates, including GSK-3, the forkhead transcription factors (FOXO), BAD, and TSC2, leading to activation of mTORC1 signaling through inhibition of the tuberous sclerosis complex (TSC1/2). mTORC1 then promotes protein synthesis through S6K and 4E-BP1 and supports anabolic metabolism.

Regulation is tightened by the lipid phosphatase PTEN, which dephosphorylates PIP3 to PIP2, and by PHLPP phosphatases that dephosphorylate Akt. Dysregulation of the PI3KAktpolku is common in cancer and metabolic diseases, contributing to uncontrolled growth and resistance to apoptosis.

Therapeutic targeting includes PI3K inhibitors, AKT inhibitors, and mTOR inhibitors (rapalogs).

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