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461  structures 1678  species 0  interactions 27225  sequences 703  architectures

Family: PI3_PI4_kinase (PF00454)

Summary: Phosphatidylinositol 3- and 4-kinase

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Phosphoinositide 3-kinase Edit Wikipedia article

Phosphatidylinositol-4,5-bisphosphate 3-kinase
PIK-93 inhibitor (yellow) bound to the PI3K 110 gamma subunit .[1]
OPM superfamily265
OPM protein3ml9
Phosphoinositide 3-kinase
EC no.
CAS no.115926-52-8
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum

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 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 gene PTEN, is implicated in the sensitivity of cancer tumors to insulin and IGF1, and in calorie restriction.[3][4]


The discovery of PI3Ks by Lewis Cantley and colleagues began with their 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 discovery that this phosphoinositide kinase had the unprecedented ability to phosphorylate phosphoinositides on the 3' position of the inositol ring.[6] Subsequently, Cantley and colleagues demonstrated that in vivo the enzyme prefers PtdIns(4,5)P2 as a substrate, producing the novel phosphoinositide PtdIns(3,4,5)P3[7] previously identified in neutrophils.[8]


The PI3K family is divided into four different classes: Class I, Class II, Class III, and Class IV. The classifications are based on primary structure, regulation, and in vitro lipid substrate specificity.[9]

Class I

Class I PI3Ks catalyze the conversion of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) into phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) in vivo. While in vitro, they have also been shown to convert phosphatidylinositol (PI) into phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 4-phosphate (PI4P) into phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P2), these reactions are strongly disfavoured in vivo.[10][11][12][13] The PI3K is activated by G protein-coupled receptors and tyrosine kinase receptors.[9]

Class I PI3Ks 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 PI3Ks are composed of a heterodimer between a p110 catalytic subunit and a p85 regulatory subunit.[14] 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 catalytic p110γ subunits comprise the class IB PI3Ks and are encoded by a single gene each (Pik3cg for p110γ and Pik3r5 for p101).

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 Y-X-X-M.[15][16]

Classes II and III

Overview of signal transduction pathways involved in apoptosis.

Class II and III PI3Ks 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 PI(4)P; 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.[17] C2α and C2β are expressed through the body, but expression of C2γ is limited to hepatocytes.

Class III PI3Ks produce 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 immune cells, not least phagocytosis.

Class IV

A group of more distantly related enzymes is sometimes referred to as class IV PI3Ks. 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
class 1 catalytic PIK3CA PI3K, catalytic, alpha polypeptide p110-α
PIK3CB PI3K, catalytic, beta polypeptide p110-β
PIK3CG PI3K, catalytic, gamma polypeptide p110-γ
PIK3CD PI3K, catalytic, delta polypeptide p110-δ
class 1 regulatory PIK3R1 PI3K, regulatory subunit 1 (alpha) p85-α N/A
PIK3R2 PI3K, regulatory subunit 2 (beta) p85-β
PIK3R3 PI3K, regulatory subunit 3 (gamma) p55-γ
PIK3R4 PI3K, regulatory subunit 4 p150
PIK3R5 PI3K, regulatory subunit 5 p101
PIK3R6 PI3K, regulatory subunit 6 p87
class 2 PIK3C2A PI3K, class 2, alpha polypeptide PI3K-C2α
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 PI3Ks (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 domains, pleckstrin homology domains (PH domains), FYVE domains or other phosphoinositide-binding domains, are recruited to various cellular membranes.


PI3Ks 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 PI3Ks 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. PI3Ks are also a key component of the insulin signaling pathway. Hence there is great interest in the role of PI3K signaling in diabetes mellitus. PI3K is also involved in interleukin signalling (IL4)[18]


The pleckstrin homology domain of AKT binds directly to PtdIns(3,4,5)P3 and PtdIns(3,4)P2, which are produced by activated PI3Ks.[19] Since PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are restricted to the plasma membrane, this 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 PI3K activation. 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 the mTOR protein kinase.

The PI3K/AKT pathway has been shown to be required for an extremely diverse array of cellular activities - most notably cellular proliferation and survival. For example, it was shown to be involved in the protection of astrocytes from ceramide-induced apoptosis.[20]

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 the O-linked N-acetylglucosamine (O-GlcNAc) transferase.

PtdIns(3,4,5)P3 also activates guanine‐nucleotide exchange factors (GEFs) that activate the GTPase Rac1,[21] leading to actin polymerization and cytoskeletal rearrangement.[22]


The class IA PI3K 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.[23] The PtdIns(3,4,5)P3 phosphatase PTEN that antagonises PI3K signaling is absent from many tumours. In addition, the epidermal growth factor receptor EGFR that functions upstream of PI3K is mutationally activated or overexpressed in cancer.[23][24] Hence, PI3K activity contributes significantly to cellular transformation and the development of cancer. It has been shown that malignant B cells maintain a "tonic" activity of PI3K/Akt axis via upregulation of an adaptor protein GAB1, and this also allows B cells to survive targeted therapy with BCR inhibitors. [25]

Learning and memory

PI3Ks have also been implicated in long-term potentiation (LTP). Whether they are required for the expression or the induction of LTP is still debated. In mouse hippocampal CA1 neurons, certain PI3Ks are complexed with AMPA receptors and compartmentalized at the postsynaptic density of glutamatergic synapses.[26] PI3Ks are phosphorylated upon NMDA receptor-dependent CaMKII activity,[27] and it then facilitates the insertion of AMPA-R GluR1 subunits into the plasma membrane. This suggests that PI3Ks are required for the expression of LTP. Furthermore, PI3K inhibitors abolished the expression of LTP in rat hippocampal CA1, but do not affect its induction.[28] Notably, the dependence of late-phase LTP expression on PI3Ks seems to decrease over time.[29]

However, another study found that PI3K inhibitors suppressed the induction, but not the expression, of LTP in mouse hippocampal CA1.[30] The PI3K pathway also recruits many other proteins downstream, including mTOR,[31] GSK3β,[32] and PSD-95.[31] The PI3K-mTOR pathway leads to the phosphorylation of p70S6K, a kinase that facilitates translational activity,[33][34] further suggesting that PI3Ks are required for the protein-synthesis phase of LTP induction instead.

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

PI 3-kinases as protein kinases

Many PI3Ks appear to have a serine/threonine kinase activity in vitro; however, it is unclear whether this has any role in vivo.[citation needed]


All PI3Ks are inhibited by the drugs wortmannin and LY294002, although certain members of the class II PI3K family show decreased sensitivity. Wortmannin shows better efficiency than LY294002 on the hotspot mutation positions (GLU542, GLU545, and HIS1047)[35][36]

PI3K inhibitors as therapeutics

As wortmannin and LY294002 are broad-range inhibitors of PI3Ks and a number of unrelated proteins at higher concentrations, they are too toxic to be used as therapeutics.[citation needed] A number of pharmaceutical companies have thus developed PI3K isoform-specific inhibitors. As of January 2019, three PI3K inhibitors are approved by the FDA for routine clinical use in humans: the PIK3CD inhibitor idelalisib (July 2014, NDA 206545), the dual PIK3CA and PIK3CD inhibitor copanlisib (September 2017, NDA 209936), and the dual PIK3CD and PIK3CG inhibitor duvelisib (September 2018, NDA 211155). Co-targeted inhibition of the pathway with other pathways such as MAPK or PIM has been highlighted as a promising anti-cancer therapeutic strategy, which could offer benefit over the monotherapeutic approach by circumventing compensatory signalling, slowing the development of resistance and potentially allowing reduction of dosing.[37][38][39][40][41][42]

See also


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Further reading

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Phosphatidylinositol 3- and 4-kinase Provide feedback

Some members of this family probably do not have lipid kinase activity and are protein kinases, e.g. P42345 [1].

Literature references

  1. Crespo JL, Hall MN; , Microbiol Mol Biol Rev 2002;66:579-591.: Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae. PUBMED:12456783 EPMC:12456783

  2. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S; , Science 2002;298:1912-1934.: The protein kinase complement of the human genome. PUBMED:12471243 EPMC:12471243

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000403

Phosphatidylinositol 3-kinase (PI3-kinase) ( EC ) [ PUBMED:1322797 ] is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. The three products of PI3-kinase - PI-3-P, PI-3,4-P(2) and PI-3,4,5-P(3) function as secondary messengers in cell signalling. Phosphatidylinositol 4-kinase (PI4-kinase) ( EC ) [ PUBMED:8194527 ] is an enzyme that acts on phosphatidylinositol (PI) in the first committed step in the production of the secondary messenger inositol-1'4'5'-trisphosphate. This domain is also present in a wide range of protein kinases, involved in diverse cellular functions, such as control of cell growth, regulation of cell cycle progression, a DNA damage checkpoint, recombination, and maintenance of telomere length. Despite significant homology to lipid kinases, no lipid kinase activity has been demonstrated for any of the PIK-related kinases [ PUBMED:12456783 ].

The PI3- and PI4-kinases share a well conserved domain at their C-terminal section; this domain seems to be distantly related to the catalytic domain of protein kinases [ PUBMED:8387896 , PUBMED:12151228 ]. The catalytic domain of PI3K has the typical bilobal structure that is seen in other ATP-dependent kinases, with a small N-terminal lobe and a large C-terminal lobe. The core of this domain is the most conserved region of the PI3Ks. The ATP cofactor binds in the crevice formed by the N-and C-terminal lobes, a loop between two strands provides a hydrophobic pocket for binding of the adenine moiety, and a lysine residue interacts with the alpha-phosphate. In contrast to protein kinases, the PI3K loop which interacts with the phosphates of the ATP and is known as the glycine-rich or P-loop, contains no glycine residues. Instead, contact with the ATP -phosphate is maintained through the side chain of a conserved serine residue.

This domain is also found in a number of pseudokinases, where a lack of typical motifs at the calatytic site suggest a lack of kinase activity.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan PKinase (CL0016), which has the following description:

This superfamily includes the Serine/Threonine- and Tyrosine- protein kinases as well as related kinases that act on non-protein substrates.

The clan contains the following 40 members:

ABC1 AceK_kinase Act-Frag_cataly Alpha_kinase APH APH_6_hur Choline_kinase CotH DUF1679 DUF2252 DUF4135 DUF5898 EcKL Fam20C Fructosamin_kin FTA2 Haspin_kinase HipA_C Ins_P5_2-kin IPK IucA_IucC Kdo Kinase-like Kinase-PolyVal KIND Pan3_PK PI3_PI4_kinase PIP49_C PIP5K PK_Tyr_Ser-Thr Pkinase Pkinase_fungal Pox_ser-thr_kin RIO1 Seadorna_VP7 TCAD9 UL97 WaaY YrbL-PhoP_reg YukC


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Representative proteomes UniProt
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

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Representative proteomes UniProt

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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Representative proteomes UniProt
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite & Pfam-B_6771 (Rlease 7.6)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Sonnhammer ELL , Finn RD
Number in seed: 41
Number in full: 27225
Average length of the domain: 205.20 aa
Average identity of full alignment: 22 %
Average coverage of the sequence by the domain: 13.49 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.1 27.1
Trusted cut-off 27.1 27.1
Noise cut-off 27.0 27.0
Model length: 250
Family (HMM) version: 30
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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The tree shows the occurrence of this domain across different species. More...


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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PI3_PI4_kinase domain has been found. There are 461 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2K344 View 3D Structure Click here
A0A0G2K5T3 View 3D Structure Click here
A0A0G2L6J0 View 3D Structure Click here
A0A0N7KPK4 View 3D Structure Click here
A0A0P0UX66 View 3D Structure Click here
A0A0P0V079 View 3D Structure Click here
A0A0P0V1M0 View 3D Structure Click here
A0A0P0W249 View 3D Structure Click here
A0A0P0XZP2 View 3D Structure Click here
A0A0R0HJJ7 View 3D Structure Click here
A0A1D6ERQ7 View 3D Structure Click here
A0A1D6GJH3 View 3D Structure Click here
A0A1D6I6H6 View 3D Structure Click here
A0A1D6M217 View 3D Structure Click here
A0A1D6MQJ4 View 3D Structure Click here
A0A1D6PS32 View 3D Structure Click here
A0A1D6Q0F2 View 3D Structure Click here
A0A1D8PDV7 View 3D Structure Click here
A0A1D8PHX3 View 3D Structure Click here
A0A1D8PTE0 View 3D Structure Click here
A0A1P8AM83 View 3D Structure Click here
A0A2R8Q370 View 3D Structure Click here
A0A2R8QL29 View 3D Structure Click here
A0A2R8QSP1 View 3D Structure Click here
A0A2R8RNC7 View 3D Structure Click here
A3A073 View 3D Structure Click here
A4HVU4 View 3D Structure Click here
A4I109 View 3D Structure Click here
A4I310 View 3D Structure Click here
A4I4K7 View 3D Structure Click here
A4I5L1 View 3D Structure Click here
A4IAC5 View 3D Structure Click here
A4IAG3 View 3D Structure Click here
A4IAK5 View 3D Structure Click here
A4IE36 View 3D Structure Click here
A4IID4 View 3D Structure Click here
A4QPH2 View 3D Structure Click here
A9X1A0 View 3D Structure Click here
B0KWC1 View 3D Structure Click here
B0UX67 View 3D Structure Click here