Phosphatidylinositol (3,4,5)-trisphosphate

Discovery

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). 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. 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.

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.

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.

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

Roles in the nervous system

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.

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.

References

References

1. (April 1988). "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate". Nature.
2. (July 1988). "An inositol tetrakisphosphate-containing phospholipid in activated neutrophils". Nature.
3. (April 1989). "PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells". Cell.
4. (January 2019). "Mitochondrial PIP3-binding protein FUNDC2 supports platelet survival via AKT signaling pathway". Cell Death and Differentiation.
5. (2020-09-07). "PTEN dephosphorylates Abi1 to promote epithelial morphogenesis". The Journal of Cell Biology.
6. (February 2016). "Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases". Biochemical Society Transactions.
7. (February 2018). "PDK1: At the crossroad of cancer signaling pathways". Seminars in Cancer Biology.
8. (April 1998). "Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase". Current Biology.
9. (January 2010). "PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane". Nature Neuroscience.
10. (13 March 2019). "PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover". Scientific Reports.