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Phosphoinositide 3-kinase

Phosphatidylinositol-4,5-bisphosphate 3-kinase (also called
phosphatidylinositide 3-kinases, phosphatidylinositol-3-kinases, PI 3-kinases,
bisphosphate 3-kinase
PI(3)Ks, PI-3Ks or by the HUGO official stem symbol for the gene family,
PI3K(s)) are a family of enzymes involved in cellular functions such as cell
growth, proliferation, differentiation, motility, survival and intracellular
trafficking, which in turn are involved in cancer.

PI3Ks are a family of related intracellular signal transducer enzymes capable of
phosphorylating the 3 position hydroxyl group of the inositol ring of
phosphatidylinositol (PtdIns).[2] The pathway, with oncogene PIK3CA and tumor
suppressor PTEN, is implicated in insensitivity of cancer tumors to insulin and
IGF1, and in calorie restriction.[3][4]

PIK-93 inhibitor (yellow) bound to the
Contents PI3 Kinase 110 gamma subunit .[1]
Class I
Symbol PI3K
Classes II and III Pfam PF00454
Class IV
InterPro IPR000403
Human genes
Mechanism SCOP 3gmm
Cancers SUPERFAMILY 3gmm
Learning and memory
OPM superfamily 265
PI 3-kinases as protein kinases
OPM protein 3ml9
PI 3-kinases inhibitors as therapeutics Available protein structures:

See also Pfam structures

References PDB RCSB PDB; PDBe; PDBj
Further reading PDBsum structure summary
External links
Phosphoinositide 3-kinase
Discovery EC number
The discovery of PI 3-kinases by Lewis Cantley and colleagues began with their CAS number 115926-52-8
identification of a previously unknown phosphoinositide kinase associated with
the polyoma middle T protein.[5] They observed unique substrate specificity and
chromatographic properties of the products of the lipid kinase, leading to the IntEnz IntEnz view
discovery that this phosphoinositide kinase had the unprecedented ability to BRENDA BRENDA entry
phosphorylate phosphoinositides on the 3' position of the inositol ring.[6] ExPASy NiceZyme view
Subsequently, Cantley and colleagues demonstrated that in vivo the enzyme MetaCyc metabolic pathway
prefers PtdIns(4,5)P2 as a substrate, producing the novel phosphoinositide PRIAM profile
PtdIns(3,4,5)P3[7] previously identified in neutrophils[8]
structures PDBsum
Classes Search
The phosphoinositol-3-kinase family is divided into four different classes: Class I, PMC articles
Class II, Class III, and Class IV. The classifications are based on primary
PubMed articles
structure, regulation, andin vitro lipid substrate specificity.[9]
NCBI proteins

Class I
Class I PI3Ks are responsible for the production of phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol (3,4)-
bisphosphate (PI(3,4)P2), and phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3).[10] The PI3K is activated by G protein-
coupled receptors and tyrosine kinase receptors.[9]

Class I PI3K are heterodimeric molecules composed of a regulatory and a catalytic subunit; they are further divided between IA and
IB subsets on sequence similarity. Class IA PI3K is composed of a heterodimer between a p110 catalytic subunit and a p85
regulatory subunit.[11] There are five variants of the p85 regulatory subunit, designated p85α, p55α, p50α, p85β, and p55γ. There are
also three variants of the p110 catalytic subunit designated p110α, β, or δ catalytic subunit. The first three regulatory subunits are all
splice variants of the same gene (Pik3r1), the other two being expressed by other genes (Pik3r2 and Pik3r3, p85β, and p55γ,
respectively). The most highly expressed regulatory subunit is p85α; all three catalytic subunits are expressed by separate genes
(Pik3ca, Pik3cb, and Pik3cd for p110α, p110β, and p110δ, respectively). The first two p110 isoforms (α and β) are expressed in all
cells, but p110δ is expressed primarily in leukocytes, and it has been suggested that it evolved in parallel with the adaptive immune
system. The regulatory p101 and catalyticp110γ subunits comprise theclass IB PI3Ks and are encoded by a single gene each.

The p85 subunits contain SH2 and SH3 domains (Online Mendelian Inheritance in Man (OMIM) 171833). The SH2 domains bind
preferentially to phosphorylated tyrosine residues in the amino acid sequence context-X-X-M.
Y [12][13]

Classes II and III
Class II and III PI3K are differentiated from the Class I by their
structure and function. The distinct feature of Class II PI3Ks is the C-
terminal C2 domain. This domain lacks critical Asp residues to
coordinate binding of Ca2+, which suggests class II PI3Ks bind lipids
in a Ca2+-independent manner.

Class II comprises three catalytic isoforms (C2α, C2β, and C2γ), but,
unlike Classes I and III, no regulatory proteins. Class II catalyse the
production of PI(3)P from PI and PI(3,4)P2 from PIP; however, little
is known about their role in immune cells. PI(3,4)P2 has, however,
been shown to play a role in the invagination phase of clathrin-
mediated endocytosis[14] . C2α and C2β are expressed through the Overview of signal transduction pathways involved
body, but expression of C2γ is limited tohepatocytes. in apoptosis.

Class III produces only PI(3)P from PI [9] but are more similar to
Class I in structure, as they exist as heterodimers of a catalytic (Vps34) and a regulatory (Vps15/p150) subunits. Class III seems to be
primarily involved in the trafficking of proteins and vesicles. There is, however, evidence to show that they are able to contribute to
the effectiveness of several process important to mmune
i cells, not leastphagocytosis.
Class IV
A group of more distantly related enzymes are sometimes referred to as class IV PI 3-kinases. It is composed of ataxia telangiectasia
mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), DNA-dependent protein kinase (DNA-PK) and mammalian target of
rapamycin (mTOR). They are protein serine/threonine kinases.

Human genes
group gene protein aliases EC number
PIK3CA PI3K, catalytic, alpha polypeptide p110-α

class 1 PIK3CB PI3K, catalytic, beta polypeptide p110-β
catalytic PIK3CG PI3K, catalytic, gamma polypeptide p110-γ
PIK3CD PI3K, catalytic, delta polypeptide p110-δ
PIK3R1 PI3K, regulatory subunit 1 (alpha) p85-α
PIK3R2 PI3K, regulatory subunit 2 (beta) p85-β

class 1 PIK3R3 PI3K, regulatory subunit 3 (gamma) p55-γ
regulatory PIK3R4 PI3K, regulatory subunit 4 p150
PIK3R5 PI3K, regulatory subunit 5 p101
PIK3R6 PI3K, regulatory subunit 6 p87
PIK3C2A PI3K, class 2, alpha polypeptide PI3K-C2α
class 2 PIK3C2B PI3K, class 2, beta polypeptide PI3K-C2β
PIK3C2G PI3K, class 2, gamma polypeptide PI3K-C2γ
class 3 PIK3C3 PI3K, class 3 Vps34

The various 3-phosphorylated phosphoinositides that are produced by PI 3-kinases (PtdIns3P, PtdIns(3,4)P2, PtdIns(3,5)P2, and
PtdIns(3,4,5)P3) function in a mechanism by which an assorted group of signalling proteins, containing PX domain, pleckstrin
homology domains (PH domains), FYVE domains and other phosphoinositide-binding domains, are recruited to various cellular

PI 3-kinases have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation,
differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ability of class I PI 3-kinases to
activate protein kinase B (PKB, aka Akt) as in the PI3K/AKT/mTOR pathway. The p110δ and p110γ isoforms regulate different
aspects of immune responses. PI 3-kinases are also a key component of the insulin signaling pathway. Hence there is great interest in
the role of PI 3-kinase signaling indiabetes mellitus.

The pleckstrin homology domainof AKT binds directly to PtdIns(3,4,5)P3 and PtdIns(3,4)P2, which are produced by activated PI 3-
kinase.[15] Since PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are restricted to the plasma membrane, these results in translocation of AKT to
the plasma membrane. Likewise, the phosphoinositide-dependent kinase-1 (PDK1 or, rarely referred to as PDPK1) also contains a
pleckstrin homology domain that binds directly to PtdIns(3,4,5)P3 and PtdIns(3,4)P2, causing it to also translocate to the plasma
membrane upon activation of PI 3-kinase. The interaction of activated PDK1 and AKT allows AKT to become phosphorylated by
PDK1 on threonine 308, leading to partial activation of AKT. Full activation of AKT occurs upon phosphorylation of serine 473 by
the TORC2 complex of themTOR protein kinase.

The "PI3-k/AKT" signaling pathway has been shown to be required for an extremely diverse array of cellular activities - most
notably cellular proliferation and survival. The phosphatidylinositol 3-kinase/protein kinase B pathway is stimulated in protection of
astrocytes from ceramide-induced apoptosis.[16]

Many other proteins have been identified that are regulated by PtdIns(3,4,5)P3, including Bruton's tyrosine kinase (BTK), General
Receptor for Phosphoinositides-1 (GRP1), and theO-linked N-acetylglucosamine (O-GlcNAc) transferase

The class IA PI 3-kinase p110α is mutated in many cancers. Many of these mutations cause the kinase to be more active. It is the
single most mutated kinase in glioblastoma, the most malignant primary brain tumor.[17] The PtdIns(3,4,5)P3 phosphatase PTEN that
antagonises PI 3-kinase signaling is absent from many tumours. In addition, the epidermal growth factor receptor EGFR that
functions upstream of PI 3-kinase is mutationally activated or overexpressed in cancer.[17][18] Hence, PI 3-kinase activity contributes
significantly to cellular transformationand the development ofcancer.

Learning and memory
PI3K has also been implicated in long-term potentiation (LTP). Whether it is required for the expression or the induction of LTP is
still debated. In mouse hippocampal CA1 neurons, PI3K is complexed with AMPA receptors and compartmentalized at the
postsynaptic density of glutamatergic synapses.[19] PI3K is phosphorylated upon NMDA receptor-dependent CaMKII activity,[20]
and it then facilitates the insertion of AMPA-R GluR1 subunits into the plasma membrane. This suggests that PI3K is required for the
expression of LTP. Furthermore, PI3K inhibitors abolished the expression of LTP in rat hippocampal CA1, but do not affect its
induction.[21] Notably, the dependence of late-phase LTP expression on PI3K seems to decrease over time.[22]

However, another study found that PI3K inhibitors suppressed the induction, but not the expression, of LTP in mouse hippocampal
CA1.[23] The PI3K pathway also recruits many other proteins downstream, including mTOR,[24] GSK3β,[25] and PSD-95.[24] The
,[26][27] further suggesting
PI3K-mTOR pathway leads to the phosphorylation ofp70S6K, a kinase that facilitates translational activity
that PI3K is required for the protein-synthesis phase of T
LP induction instead.

PI3Ks interact with theinsulin receptor substrate(IRS) to regulate glucose uptake through a series of phosphorylation events.

PI 3-kinases as protein kinases
Many of the PI 3-kinases appear to have a serine/threonine kinase activity in vitro; however, it is unclear whether this has any role in

All PI 3-kinases are inhibited by the drugs wortmannin and LY294002, although certain members of the class II PI 3-kinase family
show decreased sensitivity. Wortmannin shows better efficiency than LY294002 on the hotspot mutation positions (GLU542,
GLU545, and HIS1047)[28][29]

PI 3-kinases inhibitors as therapeutics
As wortmannin and LY294002 are broad inhibitors against PI 3-kinases and a number of unrelated proteins at higher concentrations
they are too toxic to be used as therapeutics. A number of pharmaceutical companies have recently been working on PI 3-kinase
isoform specific inhibitors including the class I PI 3-kinase, p110δ isoform specific inhibitors, IC486068 and IC87114, ICOS
Corporation.. GDC-0941 is a highly selective inhibitor of p1
10α with little activity against mTOR.

See also
PI3K/AKT/mTOR pathway

1. PDB: 2chz (; Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD,
Williams O, Loewith R, Stokoe D, Balla A, T
oth B, Balla T, Weiss WA, Williams RL, Shokat KM (2006). "A
pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling"
ov/pmc/articles/PMC2946820). Cell. 125 (4): 733–47. doi:10.1016/j.cell.2006.03.035(
06.03.035). PMC 2946820 ( . PMID 16647110 (https://ww
2. myo-inositol (
3. Giese N (2009). "Cell pathway on overdrive prevents cancer response to dietary restriction"
m/news156000728.html). Retrieved 2009-04-22.
4. Kalaany NY, Sabatini DM (April 2009)."Tumours with PI3K activation are resistant todietary restriction" (https://www. Nature. 458 (7239): 725–31. doi:10.1038/nature07782 (
0.1038/nature07782). PMC 2692085 ( . PMID 19279572 (h
5. Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM (1985). "Association of phosphatidylinositol kinase
activity with polyoma middle-T competent for transformation".Nature. 315 (6016): 239–42. doi:10.1038/315239a0 (ht
tps:// PMID 2987699 (
6. 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. doi:10.1038/332644a0 (ht
tps:// PMID 2833705 (
7. Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC (April 1989). "PDGF-dependent tyrosine phosphorylation
stimulates production of novel polyphosphoinositides in intact cells".Cell. 57 (1): 167–75. doi:10.1016/0092-
8674(89)90182-7 ( . PMID 2467744 (https://www.ncbi.nlm.nih.
8. Traynor-Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA (July 1988). "An inositol tetrakisphosphate-
containing phospholipid in activated neutrophils".Nature. 334 (6180): 353–6. doi:10.1038/334353a0 (
0.1038/334353a0). PMID 3393226 (
9. Leevers SJ, Vanhaesebroeck B, Waterfield MD (April 1999). "Signalling through phosphoinositide 3-kinases: the
lipids take centre stage".Current Opinion in Cell Biology. 11 (2): 219–25. doi:10.1016/S0955-0674(99)80029-5(http
s:// . PMID 10209156 (
10. Okkenhaug K (January 2013)."Signaling by the phosphoinositide 3-kinase family in immune cells"(https://www.ncbi. Annual Review of Immunology. 31 (2): 675–704. doi:10.1146/annurev-
immunol-032712-095946( . PMC 4516760 ( . PMID 23330955 (
11. Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaf fhausen BS, Cantley LC (November 1990). "Purification
and characterization of phosphoinositide 3-kinase from rat liver".The Journal of Biological Chemistry. 265 (32):
19704–11. PMID 2174051 (
12. Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson ,THaser WG, King F, Roberts T, Ratnofsky S, Lechleider
RJ (March 1993). "SH2 domains recognize specific phosphopeptide sequences".
Cell. 72 (5): 767–78.
doi:10.1016/0092-8674(93)90404-E( . PMID 7680959 (https://
13. Yoakim M, Hou W, Songyang Z, Liu Y, Cantley L, Schaffhausen B (September 1994)."Genetic analysis of a
phosphatidylinositol 3-kinase SH2 domain reveals determinants of specificity"
cles/PMC359119). Molecular and Cellular Biology. 14 (9): 5929–38. doi:10.1128/MCB.14.9.5929(
128/MCB.14.9.5929). PMC 359119 ( . PMID 8065326 (http
14. Cite error: The named referencepmid25264171 was invoked but never defined (see thehelp page).
15. Franke TF, Kaplan DR, Cantley LC, Toker A (January 1997). "Direct regulation of the Akt rpoto-oncogene product by
phosphatidylinositol-3,4-bisphosphate".Science. 275 (5300): 665–8. doi:10.1126/science.275.5300.665(https://doi.o
rg/10.1126/science.275.5300.665). PMID 9005852 (
16. Gómez Del Pulgar T, De Ceballos ML, Guzmán M, Velasco G (September 2002). "Cannabinoids protect astrocytes
from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway".
The Journal
of Biological Chemistry. 277 (39): 36527–33. doi:10.1074/jbc.M205797200
( PMID 12133838 (
17. Bleeker FE, Lamba S, Zanon C, Molenaar RJ, Hulsebos TJ, roost
T D, van Tilborg AA, Vandertop WP, Leenstra S,
van Noorden CJ, Bardelli A (September 2014). "Mutational profiling of kinases in glioblastoma".
BMC Cancer. 14:
718. doi:10.1186/1471-2407-14-718( PMID 25256166 (https://www.ncbi.
18. Bleeker FE, Molenaar RJ, Leenstra S (May 2012)."Recent advances in the molecular understanding of
glioblastoma" ( Journal of Neuro-Oncology. 108 (1): 11–27.
doi:10.1007/s11060-011-0793-0( PMC 3337398 (https://www.ncbi.nlm. . PMID 22270850 (
19. Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D'Souza S, Wong TP, Taghibiglou C, Lu J, Becker LE, Pei L, Liu
F, Wymann MP, MacDonald JF, Wang YT (May 2003). "Activation of PI3-kinase is required for AMP A receptor
insertion during LTP of mEPSCs in cultured hippocampal neurons". Neuron. 38 (4): 611–24. doi:10.1016/S0896-
6273(03)00228-9 ( . PMID 12765612 (
20. Joyal JL, Burks DJ, Pons S, Matter WF , Vlahos CJ, White MF, Sacks DB (November 1997). "Calmodulin activates
phosphatidylinositol 3-kinase".The Journal of Biological Chemistry. 272 (45): 28183–6.
doi:10.1074/jbc.272.45.28183( PMID 9353264 (https://www.ncbi.nlm.nih.g
21. Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, Francesconi W (May 2002).
"Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term
potentiation in the hippocampal CA1 region".The Journal of Neuroscience. 22 (9): 3359–65. PMID 11978812 (http
22. Karpova A, Sanna PP, Behnisch T (February 2006). "Involvement of multiple phosphatidylinositol 3-kinase-
dependent pathways in the persistence of late-phase long term potentiation expression".
Neuroscience. 137 (3):
833–41. doi:10.1016/j.neuroscience.2005.10.012(
PMID 16326012 (
23. Opazo P, Watabe AM, Grant SG, O'Dell TJ (May 2003). "Phosphatidylinositol 3-kinase regulates the induction of
long-term potentiation through extracellular signal-related kinase-independent mechanisms" (http://www.jneurosci.or
g/cgi/pmidlookup?view=long&pmid=12736339) . The Journal of Neuroscience. 23 (9): 3679–88. PMID 12736339 (htt
24. Yang PC, Yang CH, Huang CC, Hsu KS (February 2008). "Phosphatidylinositol 3-kinasectivation
a is required for
stress protocol-induced modification of hippocampal synaptic plasticity".
The Journal of Biological Chemistry. 283
(5): 2631–43. doi:10.1074/jbc.M706954200( PMID 18057005 (https://www.
25. Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT,
Bortolotto ZA, Wang YT, Collingridge GL (March 2007). "LTP inhibits LTD in the hippocampus via regulation of
GSK3beta". Neuron. 53 (5): 703–17. doi:10.1016/j.neuron.2007.01.029(
9). PMID 17329210 (
26. Toker A, Cantley LC (June 1997). "Signallingthrough the lipid products of phosphoinositide-3-OH kinase".Nature.
387 (6634): 673–6. doi:10.1038/42648 ( PMID 9192891 (https://www.ncbi.nlm.nih.go
27. Cammalleri M, Lütjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP (November 2003)."Time-
restricted role for dendritic activation of the mT
OR-p70S6K pathway in the induction of late-phase long-term
potentiation in the CA1"( Proceedings of the National
Academy of Sciences of the United States of America . 100 (24): 14368–73. doi:10.1073/pnas.2336098100(https://d PMC 283598 ( .
PMID 14623952 (
28. Kumar DT, Doss CG (2016-01-01). "Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at
Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach". Advances in
Protein Chemistry and Structural Biology. 102: 267–97. doi:10.1016/bs.apcsb.2015.09.008(
s.apcsb.2015.09.008). PMID 26827608 (
29. Sudhakar N, Priya Doss CG, Thirumal Kumar D, Chakraborty C, Anand K, Suresh M (2016-01-02). "Deciphering the
impact of somatic mutations in exon 20 and exon 9 of PIK3CA gene in breast tumors among Indian women through
molecular dynamics approach".Journal of Biomolecular Structure & Dynamics. 34 (1): 29–41.
doi:10.1080/07391102.2015.1007483( . PMID 25679319 (https://w

Further reading
Vanhaesebroeck B, Leevers SJ, Ahmadi K, T imms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD
(2001). "Synthesis and function of 3-phosphorylated inositol lipids".Annual Review of Biochemistry. 70: 535–602.
doi:10.1146/annurev.biochem.70.1.535. PMID 11395417. [1]
Schild C, Wirth M, Reichert M, Schmid RM, Saur D, Schneider G (December 2009). "PI3K signaling maintains c-myc
expression to regulate transcription of E2F1 in pancreatic cancer cells".
Molecular Carcinogenesis. 48 (12): 1149–
58. doi:10.1002/mc.20569. PMID 19603422.
Williams R, Berndt A, Miller S, Hon WC, Zhang X (August 2009). "Form and flexibility in phosphoinositide 3-kinases".
Biochemical Society Transactions. 37 (Pt 4): 615–26. doi:10.1042/BST0370615. PMID 19614567.
Quaresma AJ, Sievert R, Nickerson JA (April 2013)."Regulation of mRNA export by the PI3 kinase/AKT signal
transduction pathway". Molecular Biology of the Cell. 24 (8): 1208–21. doi:10.1091/mbc.E12-06-0450.
PMC 3623641 . PMID 23427269.

External links
Eukaryotic Linear Motif resourcemotif class MOD_PIKK_1
Proteopedia Phosphoinositide_3-Kinasesto explore the structure in interactive 3D
PI-3+Kinase at the US National Library of MedicineMedical Subject Headings(MeSH)
PI3K/Akt Signaling Pathway

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