regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of phosphatidylinositol 3-kinase/protein kinase B signal transduction. [GOC:ai]

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a crucial intracellular signaling cascade involved in a wide array of cellular processes, including cell growth, proliferation, survival, metabolism, and angiogenesis. This pathway is activated by various stimuli, including growth factors, hormones, and cytokines.

The activation of the PI3K/AKT pathway begins with the binding of a ligand to its receptor tyrosine kinase (RTK). This binding triggers the autophosphorylation of the RTK, which creates docking sites for adaptor proteins such as growth factor receptor-bound protein 2 (GRB2). GRB2, in turn, recruits the guanine nucleotide exchange factor (GEF) SOS, which activates the small GTPase Ras. Activated Ras then interacts with PI3K, a lipid kinase that phosphorylates phosphatidylinositol (PI) at the 3' position, generating phosphatidylinositol 3,4,5-trisphosphate (PIP3).

PIP3 serves as a docking site for the pleckstrin homology (PH) domain of AKT, bringing AKT to the plasma membrane where it can be phosphorylated and activated by the upstream kinases phosphoinositide-dependent kinase 1 (PDK1) and mammalian target of rapamycin complex 2 (mTORC2). PDK1 phosphorylates AKT at Thr308, while mTORC2 phosphorylates AKT at Ser473. These phosphorylation events fully activate AKT.

Once activated, AKT exerts its effects by phosphorylating a wide array of downstream targets, including:

- **Glycogen synthase kinase 3 (GSK3):** AKT phosphorylates GSK3, inhibiting its activity and promoting glycogen synthesis and protein synthesis.
- **Forkhead box O (FOXO) transcription factors:** AKT phosphorylates FOXO transcription factors, promoting their nuclear exclusion and inhibiting their ability to induce cell cycle arrest, apoptosis, and gluconeogenesis.
- **Tuberous sclerosis complex (TSC) 1/2:** AKT phosphorylates TSC1/2, inhibiting its activity and activating the mTORC1 complex, which promotes protein synthesis and cell growth.
- **Bad:** AKT phosphorylates Bad, inhibiting its pro-apoptotic activity and promoting cell survival.
- **Nuclear factor-κB (NF-κB):** AKT indirectly activates NF-κB, promoting inflammation and immune responses.

The PI3K/AKT pathway is tightly regulated by a variety of mechanisms to prevent its uncontrolled activation, which can contribute to cancer development and other diseases. These regulatory mechanisms include:

- **Phosphatases:** PTEN, SHIP1, and SHIP2 are phosphatases that dephosphorylate PIP3, reducing AKT activation.
- **Negative feedback loops:** AKT itself can activate feedback mechanisms that inhibit PI3K activity, such as the phosphorylation and inactivation of the scaffolding protein Gab1.
- **Ubiquitin ligases:** AKT can be targeted for degradation by ubiquitin ligases, such as MDM2 and CHIP.

Dysregulation of the PI3K/AKT pathway is implicated in various diseases, including cancer, diabetes, cardiovascular disease, and neurodegenerative disorders. Therefore, understanding the complex regulation of this pathway is crucial for developing effective therapeutic strategies for these diseases.'
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Proteins (10)

Compounds (1,046)