Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''₃), abbreviated PIP₃, is the product of the class I

phosphoinositide 3-kinases Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

' (PI 3-kinases) phosphorylation of

phosphatidylinositol (4,5)-bisphosphate Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...

(PIP₂). It is a

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

that resides on the plasma membrane.

Discovery

In 1988,

Lewis C. Cantley Lewis C. Cantley (born February 20, 1949) is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI- ...

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 Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...

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)''P''₃ is dephosphorylated by the

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...

PTEN on the 3 position, generating PI(4,5)P₂, and by SHIPs ( SH2-containing inositol phosphatase) on the 5' position of the

inositol In biochemistry, medicine, and related sciences, inositol generally refers to ''myo''-inositol (formerly ''meso''-inositol), the most important stereoisomer of the chemical compound cyclohexane-1,2,3,4,5,6-hexol. Its elemental formula, formula is ...

ring, producing PI(3,4)P₂. The

PH domain Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosph ...

in a number of proteins binds to PtdIns(3,4,5)''P''₃. Such proteins include Akt/PKB,

PDPK1 In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the ''PDPK1'' gene in humans. It is implicated in the development and progression of melanomas. Function P ...

, Btk1, and

ARNO The Arno is a river in the Tuscany region of Italy. It is the most important river of central Italy after the Tiber. Source and route The river originates on Monte Falterona in the Casentino area of the Apennines, and initially takes a sou ...

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 α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a Chemical compound, compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter Glutamate (neurotransmitter), glut ...

, contributing to

long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...

. 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 In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...

. 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

{{Phospholipids Phospholipids