Phosphoinositide 3-kinase#Class I

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.{{cite journal | vauthors = Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM | title = Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation | journal = Nature | volume = 315 | issue = 6016 | pages = 239–42 | year = 1985 | pmid = 2987699 | doi = 10.1038/315239a0 | bibcode = 1985Natur.315..239W | s2cid = 4337999 }} 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.{{cite journal | vauthors = Whitman M, Downes CP, Keeler M, Keller T, Cantley L | title = Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate | journal = Nature | volume = 332 | issue = 6165 | pages = 644–6 | date = April 1988 | pmid = 2833705 | doi = 10.1038/332644a0 | bibcode = 1988Natur.332..644W | s2cid = 4326568 }} 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{{cite journal | vauthors = Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC | title = PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells | journal = Cell | volume = 57 | issue = 1 | pages = 167–75 | date = April 1989 | pmid = 2467744 | doi = 10.1016/0092-8674(89)90182-7 | s2cid = 22154860 }} previously identified in neutrophils.{{cite journal | vauthors = Traynor-Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA | title = An inositol tetrakisphosphate-containing phospholipid in activated neutrophils | journal = Nature | volume = 334 | issue = 6180 | pages = 353–6 | date = July 1988 | pmid = 3393226 | doi = 10.1038/334353a0 | bibcode = 1988Natur.334..353T | s2cid = 4263472 }}

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.{{cite journal | vauthors = Leevers SJ, Vanhaesebroeck B, Waterfield MD | title = Signalling through phosphoinositide 3-kinases: the lipids take centre stage | journal = Current Opinion in Cell Biology | volume = 11 | issue = 2 | pages = 219–25 | date = April 1999 | pmid = 10209156 | doi = 10.1016/S0955-0674(99)80029-5 }}

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.{{cite journal | vauthors = Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT | title = The PI3K Pathway in Human Disease | journal = Cell | volume = 170 | issue = 4 | pages = 605–635 | date = August 2017 | pmid = 28802037 | pmc = 5726441 | doi = 10.1016/j.cell.2017.07.029 }}{{cite journal | vauthors = Jean S, Kiger AA | title = Classes of phosphoinositide 3-kinases at a glance | journal = Journal of Cell Science | volume = 127 | issue = Pt 5 | pages = 923–8 | date = March 2014 | pmid = 24587488 | pmc = 3937771 | doi = 10.1242/jcs.093773 }}{{cite journal | vauthors = Vanhaesebroeck B, Stephens L, Hawkins P | title = PI3K signalling: the path to discovery and understanding | journal = Nature Reviews. Molecular Cell Biology | volume = 13 | issue = 3 | pages = 195–203 | date = February 2012 | pmid = 22358332 | doi = 10.1038/nrm3290 | s2cid = 6999833 }}{{cite journal | vauthors = Okkenhaug K | title = Signaling by the phosphoinositide 3-kinase family in immune cells | journal = Annual Review of Immunology | volume = 31 | issue = 2 | pages = 675–704 | date = January 2013 | pmid = 23330955 | pmc = 4516760 | doi = 10.1146/annurev-immunol-032712-095946 }} The PI3K is activated by G protein-coupled receptors and tyrosine kinase receptors.

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 shorter regulatory subunit (often p85).{{cite journal | vauthors = Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC | title = Purification and characterization of phosphoinositide 3-kinase from rat liver | journal = The Journal of Biological Chemistry | volume = 265 | issue = 32 | pages = 19704–11 | date = November 1990 | doi = 10.1016/S0021-9258(17)45429-9 | pmid = 2174051 | doi-access = free }} There are five variants of the regulatory subunit: the three splice variants p85α, p55α, and 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 ({{OMIM|171833}}). The SH2 domains bind preferentially to phosphorylated tyrosine residues in the amino acid sequence context Y-X-X-M.{{cite journal | vauthors = Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ | display-authors = 6 | title = SH2 domains recognize specific phosphopeptide sequences | journal = Cell | volume = 72 | issue = 5 | pages = 767–78 | date = March 1993 | pmid = 7680959 | doi = 10.1016/0092-8674(93)90404-E | doi-access = free }}{{cite journal | vauthors = Yoakim M, Hou W, Songyang Z, Liu Y, Cantley L, Schaffhausen B | title = Genetic analysis of a phosphatidylinositol 3-kinase SH2 domain reveals determinants of specificity | journal = Molecular and Cellular Biology | volume = 14 | issue = 9 | pages = 5929–38 | date = September 1994 | pmid = 8065326 | pmc = 359119 | doi = 10.1128/MCB.14.9.5929 }}

Image:Signal transduction pathways.svg.]]

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.{{cite journal | vauthors = Posor Y, Eichhorn-Grünig M, Haucke V | title = Phosphoinositides in endocytosis | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 6 | pages = 794–804 | date = June 2015 | pmid = 25264171 | doi = 10.1016/j.bbalip.2014.09.014 }} 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 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.

{{Main|Phosphatidylinositol 3-kinase-related kinase}}

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.

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){{citation needed|date=October 2022}}

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.{{cite journal | vauthors = Franke TF, Kaplan DR, Cantley LC, Toker A | title = Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate | journal = Science | volume = 275 | issue = 5300 | pages = 665–8 | date = January 1997 | pmid = 9005852 | doi = 10.1126/science.275.5300.665 | s2cid = 31186873 }} 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.{{cite journal | vauthors = Gómez Del Pulgar T, De Ceballos ML, Guzmán M, Velasco G | title = Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway | journal = The Journal of Biological Chemistry | volume = 277 | issue = 39 | pages = 36527–33 | date = September 2002 | pmid = 12133838 | doi = 10.1074/jbc.M205797200 | doi-access = free }}

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,{{cite journal | vauthors = Welch HC, Coadwell WJ, Stephens LR, Hawkins PT | title = Phosphoinositide 3-kinase-dependent activation of Rac | journal = FEBS Letters | volume = 546 | issue = 1 | pages = 93–7 | date = July 2003 | pmid = 12829242 | doi = 10.1016/s0014-5793(03)00454-x | doi-access = free | bibcode = 2003FEBSL.546...93W }} leading to actin polymerization and cytoskeletal rearrangement.{{cite journal | vauthors = Jaffe AB, Hall A | title = Rho GTPases: biochemistry and biology | journal = Annual Review of Cell and Developmental Biology | volume = 21 | pages = 247–69 | date = 2005 | pmid = 16212495 | doi = 10.1146/annurev.cellbio.21.020604.150721 }}

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.{{cite journal | vauthors = Bleeker FE, Lamba S, Zanon C, Molenaar RJ, Hulsebos TJ, Troost D, van Tilborg AA, Vandertop WP, Leenstra S, van Noorden CJ, Bardelli A | display-authors = 6 | title = Mutational profiling of kinases in glioblastoma | journal = BMC Cancer | volume = 14 | pages = 718 | date = September 2014 | pmid = 25256166 | pmc = 4192443 | doi = 10.1186/1471-2407-14-718 | doi-access = free }} 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.{{cite journal | vauthors = Bleeker FE, Molenaar RJ, Leenstra S | title = Recent advances in the molecular understanding of glioblastoma | journal = Journal of Neuro-Oncology | volume = 108 | issue = 1 | pages = 11–27 | date = May 2012 | pmid = 22270850 | pmc = 3337398 | doi = 10.1007/s11060-011-0793-0 }} 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.{{citation needed|date=October 2022}}

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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons | journal = Neuron | volume = 38 | issue = 4 | pages = 611–24 | date = May 2003 | pmid = 12765612 | doi = 10.1016/S0896-6273(03)00228-9 | doi-access = free }}

PI3Ks are phosphorylated upon NMDA receptor-dependent CaMKII activity,{{cite journal | vauthors = Joyal JL, Burks DJ, Pons S, Matter WF, Vlahos CJ, White MF, Sacks DB | title = Calmodulin activates phosphatidylinositol 3-kinase | journal = The Journal of Biological Chemistry | volume = 272 | issue = 45 | pages = 28183–6 | date = November 1997 | pmid = 9353264 | doi = 10.1074/jbc.272.45.28183 | doi-access = free }} 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.{{cite journal | vauthors = Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, Francesconi W | title = 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 | journal = The Journal of Neuroscience | volume = 22 | issue = 9 | pages = 3359–65 | date = May 2002 | pmid = 11978812 | pmc = 6758361 | doi = 10.1523/JNEUROSCI.22-09-03359.2002 }} Notably, the dependence of late-phase LTP expression on PI3Ks seems to decrease over time.{{cite journal | vauthors = Karpova A, Sanna PP, Behnisch T | title = Involvement of multiple phosphatidylinositol 3-kinase-dependent pathways in the persistence of late-phase long term potentiation expression | journal = Neuroscience | volume = 137 | issue = 3 | pages = 833–41 | date = February 2006 | pmid = 16326012 | doi = 10.1016/j.neuroscience.2005.10.012 | s2cid = 38232127 }}

However, another study found that PI3K inhibitors suppressed the induction, but not the expression, of LTP in mouse hippocampal CA1.{{cite journal | vauthors = Opazo P, Watabe AM, Grant SG, O'Dell TJ | title = Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms | journal = The Journal of Neuroscience | volume = 23 | issue = 9 | pages = 3679–88 | date = May 2003 | pmid = 12736339 | pmc = 6742185 | doi = 10.1523/JNEUROSCI.23-09-03679.2003 }} The PI3K pathway also recruits many other proteins downstream, including mTOR,{{cite journal | vauthors = Yang PC, Yang CH, Huang CC, Hsu KS | title = Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity | journal = The Journal of Biological Chemistry | volume = 283 | issue = 5 | pages = 2631–43 | date = February 2008 | pmid = 18057005 | doi = 10.1074/jbc.M706954200 | doi-access = free }} GSK3β,{{cite journal | vauthors = 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 | display-authors = 6 | title = LTP inhibits LTD in the hippocampus via regulation of GSK3beta | journal = Neuron | volume = 53 | issue = 5 | pages = 703–17 | date = March 2007 | pmid = 17329210 | doi = 10.1016/j.neuron.2007.01.029 | s2cid = 6903401 | url = http://www.hal.inserm.fr/inserm-00776885 | doi-access = free }} and PSD-95. The PI3K-mTOR pathway leads to the phosphorylation of p70S6K, a kinase that facilitates translational activity,{{cite journal | vauthors = Toker A, Cantley LC | title = Signalling through the lipid products of phosphoinositide-3-OH kinase | journal = Nature | volume = 387 | issue = 6634 | pages = 673–6 | date = June 1997 | pmid = 9192891 | doi = 10.1038/42648 | bibcode = 1997Natur.387..673T | s2cid = 4347728 | doi-access = free }}{{cite journal | vauthors = Cammalleri M, Lütjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP | title = Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 24 | pages = 14368–73 | date = November 2003 | pmid = 14623952 | pmc = 283598 | doi = 10.1073/pnas.2336098100 | bibcode = 2003PNAS..10014368C | doi-access = free }} 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.

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|date=January 2019}}

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){{cite book | vauthors = Kumar DT, Doss CG | title = Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach | journal = Advances in Protein Chemistry and Structural Biology | volume = 102 | pages = 267–97 | date = 2016-01-01 | pmid = 26827608 | doi = 10.1016/bs.apcsb.2015.09.008 | isbn = 9780128047958 }}{{cite journal | vauthors = Sudhakar N, Priya Doss CG, Thirumal Kumar D, Chakraborty C, Anand K, Suresh M | title = 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 = Journal of Biomolecular Structure & Dynamics | volume = 34 | issue = 1 | pages = 29–41 | date = 2016-01-02 | pmid = 25679319 | doi = 10.1080/07391102.2015.1007483 | s2cid = 205575161 }}

{{Main|PI3K inhibitor}}

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|date=July 2010}} 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, [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=206545 NDA 206545]), the dual PIK3CA and PIK3CD inhibitor copanlisib (September 2017, [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209936 NDA 209936]), and the dual PIK3CD and PIK3CG inhibitor duvelisib (September 2018, [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211155 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.{{cite journal | vauthors = Malone T, Schäfer L, Simon N, Heavey S, Cuffe S, Finn S, Moore G, Gately K | display-authors = 6 | title = Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer | journal = Pharmacology & Therapeutics | volume = 207 | pages = 107454 | date = March 2020 | pmid = 31836451 | doi = 10.1016/j.pharmthera.2019.107454 | s2cid = 209357486 | url = https://discovery.ucl.ac.uk/id/eprint/10088376/1/1-s2.0-S0163725819302062-main.pdf }}{{cite journal | vauthors = Luszczak S, Kumar C, Sathyadevan VK, Simpson BS, Gately KA, Whitaker HC, Heavey S | title = PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer | journal = Signal Transduction and Targeted Therapy | volume = 5 | pages = 7 | date = 2020 | pmid = 32025342 | pmc = 6992635 | doi = 10.1038/s41392-020-0109-y }}{{cite journal | vauthors = Heavey S, Dowling P, Moore G, Barr MP, Kelly N, Maher SG, Cuffe S, Finn SP, O'Byrne KJ, Gately K | display-authors = 6 | title = Development and characterisation of a panel of phosphatidylinositide 3-kinase - mammalian target of rapamycin inhibitor resistant lung cancer cell lines | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 1652 | date = January 2018 | pmid = 29374181 | pmc = 5786033 | doi = 10.1038/s41598-018-19688-1 | bibcode = 2018NatSR...8.1652H }}{{cite journal | vauthors = Heavey S, Godwin P, Baird AM, Barr MP, Umezawa K, Cuffe S, Finn SP, O'Byrne KJ, Gately K | display-authors = 6 | title = Strategic targeting of the PI3K-NFκB axis in cisplatin-resistant NSCLC | journal = Cancer Biology & Therapy | volume = 15 | issue = 10 | pages = 1367–77 | date = October 2014 | pmid = 25025901 | pmc = 4130730 | doi = 10.4161/cbt.29841 }}{{cite journal | vauthors = Heavey S, O'Byrne KJ, Gately K | title = Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC | journal = Cancer Treatment Reviews | volume = 40 | issue = 3 | pages = 445–56 | date = April 2014 | pmid = 24055012 | doi = 10.1016/j.ctrv.2013.08.006 }}

• PI3K/AKT/mTOR pathway

{{Reflist|33em}}

{{refbegin|33em}}

• {{cite journal | vauthors = Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD | display-authors = 6 | title = Synthesis and function of 3-phosphorylated inositol lipids | journal = Annual Review of Biochemistry | volume = 70 | pages = 535–602 | year = 2001 | pmid = 11395417 | doi = 10.1146/annurev.biochem.70.1.535 }} [http://arjournals.annualreviews.org/doi/abs/10.1146%2Fannurev.biochem.70.1.535]
• {{cite journal | vauthors = Schild C, Wirth M, Reichert M, Schmid RM, Saur D, Schneider G | title = PI3K signaling maintains c-myc expression to regulate transcription of E2F1 in pancreatic cancer cells | journal = Molecular Carcinogenesis | volume = 48 | issue = 12 | pages = 1149–58 | date = December 2009 | pmid = 19603422 | doi = 10.1002/mc.20569 | s2cid = 41545085 }}
• {{cite journal | vauthors = Williams R, Berndt A, Miller S, Hon WC, Zhang X | title = Form and flexibility in phosphoinositide 3-kinases | journal = Biochemical Society Transactions | volume = 37 | issue = Pt 4 | pages = 615–26 | date = August 2009 | pmid = 19614567 | doi = 10.1042/BST0370615 }}
• {{cite journal | vauthors = Quaresma AJ, Sievert R, Nickerson JA | title = Regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway | journal = Molecular Biology of the Cell | volume = 24 | issue = 8 | pages = 1208–21 | date = April 2013 | pmid = 23427269 | pmc = 3623641 | doi = 10.1091/mbc.E12-06-0450 }}

{{refend}}

• {{ELM|MOD_PIKK_1}}
• {{Proteopedia|Phosphoinositide_3-Kinases}} to explore the structure in interactive 3D
• {{MeshName|PI-3+Kinase}}
• [http://www.cellsignal.com/reference/pathway/Akt_PKB.html PI3K/Akt Signaling Pathway]

{{Kinases}}

{{Enzymes}}

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{{DEFAULTSORT:Phosphoinositide 3-Kinase}}

Category:EC 2.7.1

Category:Oncology