PIK3C2A explained

Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the PIK3C2A gene.^{[1] [2]}

The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking.

This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of Class II PI 3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. The PI3-kinase activity of this protein is not sensitive to nanomolar levels of the inhibitor wortmannin. This protein was shown to be able to be activated by insulin and may be involved in integrin-dependent signaling.^[2]

Clinical significance

Three families have been reported with homozygous loss of function mutations in this gene.^[3] The clinical features of this syndrome include short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities and neurological manifestations. Abnormalities of cilial function were also noted.

Further reading

• Lee C . Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways . J. Leukoc. Biol. . 74 . 5 . 676–682 . 2004 . 12960231 . 10.1189/jlb.0503206 . vanc. Liu QH . Tomkowicz B . 3 . Yi . Y . Freedman . BD . Collman . RG . 11362623 . free .
• Milani D . Extracellular human immunodeficiency virus type-1 Tat protein activates phosphatidylinositol 3-kinase in PC12 neuronal cells . J. Biol. Chem. . 271 . 38 . 22961–22964 . 1996 . 8798481 . 10.1074/jbc.271.38.22961 . vanc. Mazzoni M . Borgatti P . 3 . Zauli . G . Cantley . L . Capitani . S . free .
• Mazerolles F, Barbat C, Fischer A . Down-regulation of LFA-1-mediated T cell adhesion induced by the HIV envelope glycoprotein gp160 requires phosphatidylinositol-3-kinase activity . Eur. J. Immunol. . 27 . 9 . 2457–2465 . 1997 . 9341793 . 10.1002/eji.1830270946 . 33397908 .
• Borgatti P . Extracellular HIV-1 Tat protein activates phosphatidylinositol 3- and Akt/PKB kinases in CD4+ T lymphoblastoid Jurkat cells . Eur. J. Immunol. . 27 . 11 . 2805–2811 . 1998 . 9394803 . 10.1002/eji.1830271110 . vanc. Zauli G . Colamussi ML . 3 . Gibellini . Davide . Previati . Maurizio . Cantley . Lewis L. . Capitani . Silvano . 6303471 .
• Borgatti P, Zauli G, Cantley LC, Capitani S . Extracellular HIV-1 Tat protein induces a rapid and selective activation of protein kinase C (PKC)-alpha, and -epsilon and -zeta isoforms in PC12 cells . Biochem. Biophys. Res. Commun. . 242 . 2 . 332–337 . 1998 . 9446795 . 10.1006/bbrc.1997.7877 .
• Zhang J . A type II phosphoinositide 3-kinase is stimulated via activated integrin in platelets. A source of phosphatidylinositol 3-phosphate . J. Biol. Chem. . 273 . 23 . 14081–14084 . 1998 . 9603905 . 10.1074/jbc.273.23.14081 . vanc. Banfić H . Straforini F . 3 . Tosi . L . Volinia . S . Rittenhouse . SE . free .
• Milani D . HIV-1 Tat induces tyrosine phosphorylation of p125FAK and its association with phosphoinositide 3-kinase in PC12 cells . AIDS . 12 . 11 . 1275–1284 . 1998 . 9708406 . 10.1097/00002030-199811000-00008 . vanc. Mazzoni M . Zauli G . 3 . Mischiati . Carlo . Gibellini . Davide . Giacca . Mauro . Capitani . Silvano . 25758704 . free .
• Jauliac S . Ligands of CD4 inhibit the association of phospholipase Cgamma1 with phosphoinositide 3 kinase in T cells: regulation of this association by the phosphoinositide 3 kinase activity . Eur. J. Immunol. . 28 . 10 . 3183–3191 . 1998 . 9808187 . 10.1002/(SICI)1521-4141(199810)28:10<3183::AID-IMMU3183>3.0.CO;2-A . vanc. Mazerolles F . Jabado N . 3 . Pallier . Annaïck . Bernard . Frédéric . Peake . Jane . Fischer . Alain . Hivroz . Claire . free .
• Brown RA . Insulin activates the alpha isoform of class II phosphoinositide 3-kinase . J. Biol. Chem. . 274 . 21 . 14529–14532 . 1999 . 10329640 . 10.1074/jbc.274.21.14529 . vanc. Domin J . Arcaro A . 3 . Waterfield . MD . Shepherd . PR . free.
• Idriss H . HIV-1 reverse transcriptase is phosphorylated in vitro and in a cellular system . Int. J. Biochem. Cell Biol. . 31 . 12 . 1443–1452 . 2000 . 10641798 . 10.1016/S1357-2725(99)00097-7 . vanc. Kawa S . Damuni Z . 3 . Thompson . EB . Wilson . SH .
• Domin J . The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans-Golgi network and present in clathrin-coated vesicles . J. Biol. Chem. . 275 . 16 . 11943–11950 . 2000 . 10766823 . 10.1074/jbc.275.16.11943 . vanc. Gaidarov I . Smith ME . 3 . Keen . JH . Waterfield . MD . free.
• Arcaro A . Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors . Mol. Cell. Biol. . 20 . 11 . 3817–3830 . 2000 . 10805725 . 10.1128/MCB.20.11.3817-3830.2000 . 85707 . vanc. Zvelebil MJ . Wallasch C . 3 . Ullrich . A. . Waterfield . M. D. . Domin . J. .
• Park IW, Wang JF, Groopman JE . HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes . Blood . 97 . 2 . 352–358 . 2001 . 11154208 . 10.1182/blood.V97.2.352 . free .
• Zauli G . HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway . FASEB J. . 15 . 2 . 483–491 . 2001 . 11156964 . 10.1096/fj.00-0354com . vanc. Milani D . Mirandola P . 3 . Mazzoni . M . Secchiero . P . Miscia . S . Capitani . S . free . 26315564 .
• Gaidarov I, Smith ME, Domin J, Keen JH . The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking . Mol. Cell . 7 . 2 . 443–449 . 2001 . 11239472 . 10.1016/S1097-2765(01)00191-5 . free .
• Caldwell GM . Mapping of genes and transcribed sequences in a gene rich 400-kb region on human chromosome 11p15.1→p14 . Cytogenet. Cell Genet. . 92 . 1–2 . 103–107 . 2001 . 11306805 . 10.1159/000056877 . vanc. Eddy RL . Day CD . 3 . Haley . L.H. . Cooper . P.R. . Sait . S.S.J. . Hejtmancik . F. . Smith . R.J.H. . Morton . C.C. . 46081338 .
• Didichenko SA, Thelen M . Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization sequence and associates with nuclear speckles . J. Biol. Chem. . 276 . 51 . 48135–42 . 2002 . 11606566 . 10.1074/jbc.M104610200 . free .
• Deregibus MC . HIV-1-Tat protein activates phosphatidylinositol 3-kinase/ AKT-dependent survival pathways in Kaposi's sarcoma cells . J. Biol. Chem. . 277 . 28 . 25195–25202 . 2002 . 11994280 . 10.1074/jbc.M200921200 . vanc. Cantaluppi V . Doublier S . 3 . Brizzi . MF . Deambrosis . I . Albini . A . Camussi . G . free .
• Cook JA, August A, Henderson AJ . Recruitment of phosphatidylinositol 3-kinase to CD28 inhibits HIV transcription by a Tat-dependent mechanism . J. Immunol. . 169 . 1 . 254–60 . 2002 . 12077252 . 10.4049/jimmunol.169.1.254. free .

Notes and References

1. Domin J, Pages F, Volinia S, Rittenhouse SE, Zvelebil MJ, Stein RC, Waterfield MD . Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin . Biochem J . 326 . 1. 139–47 . Nov 1997 . 9337861 . 1218647 . 10.1042/bj3260139.
2. Web site: Entrez Gene: PIK3C2A phosphoinositide-3-kinase, class 2, alpha polypeptide.
3. Tiosano D, Baris HN, Chen A, Hitzert MM, Schueler M, Gulluni F, Wiesener A, Bergua A, Mory A, Copeland B, Gleeson JG, Rump P, van Meer H, Sival DA, Haucke V, Kriwinsky J, Knaup KX, Reis A, Hauer NN, Hirsch E, Roepman R, Pfundt R, Thiel CT, Wiesener MS, Aslanyan MG, Buchner DA . 6 . Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction . PLOS Genetics . 15 . 4 . e1008088 . April 2019 . 31034465 . 6508738 . 10.1371/journal.pgen.1008088 . free .