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

that resides on the plasma membrane.

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 Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying i ...

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 Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tr ...

, 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 monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Ph ...

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

inositol Inositol, or more precisely ''myo''-inositol, is a carbocyclic sugar that is abundant in the brain and other mammalian tissues; it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors an ...

ring, producing PI(3,4)P₂. The

PH domain In chemistry, pH (), historically denoting "potential of hydrogen" (or "power of hydrogen"), is a scale used to specify the acidity or basicity of an aqueous solution. Acidic solutions (solutions with higher concentrations of ions) are ...

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 so ...

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 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 neurons ...

. 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 strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circui ...

. 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