Phosphatidylinositol (3,4,5)-trisphosphate

In 1988, Lewis C. Cantley published a paper describing the discovery of a novel type of phosphoinositide kinase with the unprecedented ability to phosphorylate the 3' position of the inositol ring resulting in the formation of phosphatidylinositol-3-phosphate (PI3P).^[1] Working independently, Alexis Traynor-Kaplan and coworkers published a paper demonstrating that a novel lipid, phosphatidylinositol 3,4,5 trisphosphate (PIP3) occurs naturally in human neutrophils with levels that increased rapidly following physiologic stimulation with chemotactic peptide.^[2] Subsequent studies demonstrated that in vivo the enzyme originally identified by Cantley's group prefers PtdIns(4,5)P2 as a substrate, producing the product PIP3.^[3]

PIP₃ functions to activate downstream signaling components, the most notable one being the protein kinase Akt, which activates downstream anabolic signaling pathways required for cell growth and survival.^[4]

PtdIns(3,4,5)P₃ is dephosphorylated by the phosphatase PTEN on the 3 position, generating PI(4,5)P₂, and by SHIPs (SH2-containing inositol phosphatase) on the 5' position of the inositol ring, producing PI(3,4)P₂.^[5]

The PH domain in a number of proteins binds to PtdIns(3,4,5)P₃. Such proteins include Akt/PKB,^[6] PDPK1,^[7] Btk1, and ARNO.^[8]

PIP3 plays a critical role outside the cytosol, notably at the postsynaptic terminal of hippocampal cells. Here, PIP3 has been implicated in regulating synaptic strengthening and AMPA expression, contributing to long-term potentiation. Moreover, PIP3 suppression disrupts normal AMPA expression on the neuron membrane and instead leads to the accumulation of AMPA on dendritic spines, commonly associated with synaptic depression.^[9]

PIP3 interacts with proteins to mediate synaptic plasticity. Of these proteins, Phldb2 has been shown to interact with PIP3 to induce and maintain long-term potentiation. In the absence of such an interaction, memory consolidation is impaired.^[10]