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Phosphoinositide 3-kinase

Phosphatidylinositol-4,5-bisphosphate 3-kinase (also called
Phosphatidylinositol-4,5-
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]
Discovery
Identifiers
Classes
Class I
Symbol PI3K
Classes II and III Pfam PF00454
Class IV
InterPro IPR000403
Human genes
SMART SM00146
Mechanism
PROSITE PDOC00710
Function
Mechanism SCOP 3gmm
Cancers SUPERFAMILY 3gmm
Learning and memory
OPM superfamily 265
PI 3-kinases as protein kinases
OPM protein 3ml9
Inhibition
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
Identifiers
Discovery EC number 2.7.1.137
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
Databases
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
KEGG KEGG entry
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]
PDB RCSB PDB PDBe
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
2.7.1.153
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
N/A
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 2.7.1.154
PIK3C2G PI3K, class 2, gamma polypeptide PI3K-C2γ
class 3 PIK3C3 PI3K, class 3 Vps34 2.7.1.137

Mechanism
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
membranes.

Function
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.

Mechanism
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
.

Cancers
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
vivo.

Inhibition
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

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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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