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]
Function
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]
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]
References
^Whitman M, Downes CP, Keeler M, Keller T, Cantley L (April 1988). "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate". Nature. 332 (6165): 644–6.
Bibcode:
1988Natur.332..644W.
doi:
10.1038/332644a0.
PMID2833705.
S2CID4326568.