Summary: Phosphatidylinositol 3- and 4-kinase
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "Phosphoinositide 3-kinase". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at firstname.lastname@example.org and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Phosphoinositide 3-kinase Edit Wikipedia article
PIK-93 inhibitor (yellow) bound to the PI3K 110 gamma subunit .
|SCOPe||3gmm / SUPFAM|
|PDB structures||RCSB 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). The pathway, with oncogene PIK3CA and tumor suppressor PTEN, is implicated in the sensitivity of cancer tumors to insulin and IGF1, and in calorie restriction.
- 1 Discovery
- 2 Classes
- 3 Human genes
- 4 Mechanism
- 5 Function
- 6 PI 3-kinases as protein kinases
- 7 Inhibition
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
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. 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. 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 previously identified in neutrophils
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.
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. 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 p85 regulatory subunit. There are five variants of the p85 regulatory subunit, designated p85Î±, p55Î±, p50Î±, p85Î², and p55Î³. There are also three variants of the p110 catalytic subunit designated p110Î±, Î², or Î´ 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, p85Î², and p55Î³, respectively). The most highly expressed regulatory subunit is p85Î±; all three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb, and Pik3cd for p110Î±, p110Î², and p110Î´, respectively). The first two p110 isoforms (Î± and Î²) are expressed in all cells, but p110Î´ 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 p110Î³ subunits comprise the class IB PI3Ks and are encoded by a single gene each (Pik3cg for p110Î³ 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.
Classes II and III
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 (C2Î±, C2Î², and C2Î³), 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. C2Î± and C2Î² are expressed through the body, but expression of C2Î³ 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.
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.
|class 1 catalytic||PIK3CA||PI3K, catalytic, alpha polypeptide||p110-Î±||188.8.131.52|
|PIK3CB||PI3K, catalytic, beta polypeptide||p110-Î²|
|PIK3CG||PI3K, catalytic, gamma polypeptide||p110-Î³|
|PIK3CD||PI3K, catalytic, delta polypeptide||p110-Î´|
|class 1 regulatory||PIK3R1||PI3K, regulatory subunit 1 (alpha)||p85-Î±||N/A|
|PIK3R2||PI3K, regulatory subunit 2 (beta)||p85-Î²|
|PIK3R3||PI3K, regulatory subunit 3 (gamma)||p55-Î³|
|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-C2Î±||184.108.40.206|
|PIK3C2B||PI3K, class 2, beta polypeptide||PI3K-C2Î²|
|PIK3C2G||PI3K, class 2, gamma polypeptide||PI3K-C2Î³|
|class 3||PIK3C3||PI3K, class 3||Vps34||220.127.116.11|
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 p110Î´ and p110Î³ 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.
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. 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.
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.
The class IA PI3K p110Î± 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. 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. Hence, PI3K activity contributes significantly to cellular transformation and the development of cancer.
Learning and memory
PI3Ks have also been implicated in long-term potentiation (LTP). Whether it 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. PI3Ks are phosphorylated upon NMDA receptor-dependent CaMKII activity, 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. Notably, the dependence of late-phase LTP expression on PI3Ks seems to decrease over time.
However, another study found that PI3K inhibitors suppressed the induction, but not the expression, of LTP in mouse hippocampal CA1. The PI3K pathway also recruits many other proteins downstream, including mTOR, GSK3Î², and PSD-95. The PI3K-mTOR pathway leads to the phosphorylation of p70S6K, a kinase that facilitates translational activity, 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.
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)
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. 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).
- "A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling". Cell. 125 (4): 733â€“47. doi:10.1016/j.cell.2006.03.035. PMC 2946820. PMID 16647110. ; Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, et al. (May 2006).
- Giese N (2009). "Cell pathway on overdrive prevents cancer response to dietary restriction". PhysOrg.com. Retrieved 2009-04-22.
- Kalaany NY, Sabatini DM (April 2009). "Tumours with PI3K activation are resistant to dietary restriction". Nature. 458 (7239): 725â€“31. Bibcode:2009Natur.458..725K. doi:10.1038/nature07782. PMC 2692085. PMID 19279572.
- 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): 239â€“42. Bibcode:1985Natur.315..239W. doi:10.1038/315239a0. PMID 2987699.
- 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): 644â€“6. Bibcode:1988Natur.332..644W. doi:10.1038/332644a0. PMID 2833705.
- 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): 167â€“75. doi:10.1016/0092-8674(89)90182-7. PMID 2467744.
- Traynor-Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA (July 1988). "An inositol tetrakisphosphate-containing phospholipid in activated neutrophils". Nature. 334 (6180): 353â€“6. Bibcode:1988Natur.334..353T. doi:10.1038/334353a0. PMID 3393226.
- 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): 219â€“25. doi:10.1016/S0955-0674(99)80029-5. PMID 10209156.
- Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT (August 2017). "The PI3K Pathway in Human Disease". Cell. 170 (4): 605â€“635. doi:10.1016/j.cell.2017.07.029. PMC 5726441. PMID 28802037.
- Jean S, Kiger AA (March 2014). "Classes of phosphoinositide 3-kinases at a glance". Journal of Cell Science. 127 (Pt 5): 923â€“8. doi:10.1242/jcs.093773. PMC 3937771. PMID 24587488.
- Vanhaesebroeck B, Stephens L, Hawkins P (February 2012). "PI3K signalling: the path to discovery and understanding". Nature Reviews. Molecular Cell Biology. 13 (3): 195â€“203. doi:10.1038/nrm3290. PMID 22358332.
- Okkenhaug K (January 2013). "Signaling by the phosphoinositide 3-kinase family in immune cells". Annual Review of Immunology. 31 (2): 675â€“704. doi:10.1146/annurev-immunol-032712-095946. PMC 4516760. PMID 23330955.
- Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC (November 1990). "Purification and characterization of phosphoinositide 3-kinase from rat liver". The Journal of Biological Chemistry. 265 (32): 19704â€“11. PMID 2174051.
- Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, et al. (March 1993). "SH2 domains recognize specific phosphopeptide sequences". Cell. 72 (5): 767â€“78. doi:10.1016/0092-8674(93)90404-E. PMID 7680959.
- 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". Molecular and Cellular Biology. 14 (9): 5929â€“38. doi:10.1128/MCB.14.9.5929. PMC 359119. PMID 8065326.
- Posor Y, Eichhorn-GrÃ¼nig M, Haucke V (June 2015). "Phosphoinositides in endocytosis". Biochimica et Biophysica Acta. 1851 (6): 794â€“804. doi:10.1016/j.bbalip.2014.09.014. PMID 25264171.
- Franke TF, Kaplan DR, Cantley LC, Toker A (January 1997). "Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate". Science. 275 (5300): 665â€“8. doi:10.1126/science.275.5300.665. PMID 9005852.
- GÃ³mez Del Pulgar T, De Ceballos ML, GuzmÃ¡n 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): 36527â€“33. doi:10.1074/jbc.M205797200. PMID 12133838.
- Welch HC, Coadwell WJ, Stephens LR, Hawkins PT (July 2003). "Phosphoinositide 3-kinase-dependent activation of Rac". FEBS Letters. 546 (1): 93â€“7. doi:10.1016/s0014-5793(03)00454-x. PMID 12829242.
- Jaffe AB, Hall A (2005). "Rho GTPases: biochemistry and biology". Annual Review of Cell and Developmental Biology. 21: 247â€“69. doi:10.1146/annurev.cellbio.21.020604.150721. PMID 16212495.
- Bleeker FE, Lamba S, Zanon C, Molenaar RJ, Hulsebos TJ, Troost D, et al. (September 2014). "Mutational profiling of kinases in glioblastoma". BMC Cancer. 14: 718. doi:10.1186/1471-2407-14-718. PMC 4192443. PMID 25256166.
- Bleeker FE, Molenaar RJ, Leenstra S (May 2012). "Recent advances in the molecular understanding of glioblastoma". Journal of Neuro-Oncology. 108 (1): 11â€“27. doi:10.1007/s11060-011-0793-0. PMC 3337398. PMID 22270850.
- Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, et al. (May 2003). "Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons". Neuron. 38 (4): 611â€“24. doi:10.1016/S0896-6273(03)00228-9. PMID 12765612.
- 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): 28183â€“6. doi:10.1074/jbc.272.45.28183. PMID 9353264.
- 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): 3359â€“65. doi:10.1523/JNEUROSCI.22-09-03359.2002. PMC 6758361. PMID 11978812.
- 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): 833â€“41. doi:10.1016/j.neuroscience.2005.10.012. PMID 16326012.
- 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". The Journal of Neuroscience. 23 (9): 3679â€“88. doi:10.1523/JNEUROSCI.23-09-03679.2003. PMC 6742185. PMID 12736339.
- Yang PC, Yang CH, Huang CC, Hsu KS (February 2008). "Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity". The Journal of Biological Chemistry. 283 (5): 2631â€“43. doi:10.1074/jbc.M706954200. PMID 18057005.
- Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, et al. (March 2007). "LTP inhibits LTD in the hippocampus via regulation of GSK3beta". Neuron. 53 (5): 703â€“17. doi:10.1016/j.neuron.2007.01.029. PMID 17329210.
- Toker A, Cantley LC (June 1997). "Signalling through the lipid products of phosphoinositide-3-OH kinase". Nature. 387 (6634): 673â€“6. Bibcode:1997Natur.387..673T. doi:10.1038/42648. PMID 9192891.
- Cammalleri M, LÃ¼tjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP (November 2003). "Time-restricted role for dendritic activation of the mTOR-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): 14368â€“73. Bibcode:2003PNAS..10014368C. doi:10.1073/pnas.2336098100. PMC 283598. PMID 14623952.
- 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. pp. 267â€“97. doi:10.1016/bs.apcsb.2015.09.008. ISBN 9780128047958. PMID 26827608.
- 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): 29â€“41. doi:10.1080/07391102.2015.1007483. PMID 25679319.
- Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, et al. (2001). "Synthesis and function of 3-phosphorylated inositol lipids". Annual Review of Biochemistry. 70: 535â€“602. doi:10.1146/annurev.biochem.70.1.535. PMID 11395417. 
- 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): 1149â€“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): 615â€“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): 1208â€“21. doi:10.1091/mbc.E12-06-0450. PMC 3623641. PMID 23427269.
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
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.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
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 38 members:ABC1 AceK Act-Frag_cataly Alpha_kinase APH APH_6_hur Choline_kinase CotH DUF1679 DUF2252 DUF4135 EcKinase 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 Pkinase Pkinase_fungal Pkinase_Tyr Pox_ser-thr_kin RIO1 Seadorna_VP7 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, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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...
If you find these logos useful in your own work, please consider citing the following article:
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.
|Seed source:||Prosite & Pfam-B_6771 (Rlease 7.6)|
|Author:||Sonnhammer ELL , Finn RD|
|Number in seed:||41|
|Number in full:||14800|
|Average length of the domain:||208.30 aa|
|Average identity of full alignment:||22 %|
|Average coverage of the sequence by the domain:||13.64 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||27|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 12 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 329 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.
Loading structure mapping...