Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''
3), abbreviated PIP
3, 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 ...
(PIP
2). 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
PIP
3 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