PI42A_HUMAN
ID PI42A_HUMAN Reviewed; 406 AA.
AC P48426; B0YJ66; B4DGX2; D3DRV1; P53807; Q5VUX3;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 14-AUG-2001, sequence version 2.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha {ECO:0000305};
DE EC=2.7.1.149 {ECO:0000269|PubMed:9367159};
DE AltName: Full=1-phosphatidylinositol 5-phosphate 4-kinase 2-alpha;
DE AltName: Full=Diphosphoinositide kinase 2-alpha;
DE AltName: Full=PIP5KIII;
DE AltName: Full=Phosphatidylinositol 5-Phosphate 4-Kinase;
DE Short=PI5P4Kalpha;
DE AltName: Full=Phosphatidylinositol 5-phosphate 4-kinase type II alpha;
DE Short=PI(5)P 4-kinase type II alpha;
DE Short=PIP4KII-alpha;
DE AltName: Full=PtdIns(4)P-5-kinase B isoform;
DE AltName: Full=PtdIns(4)P-5-kinase C isoform;
DE AltName: Full=PtdIns(5)P-4-kinase isoform 2-alpha;
GN Name=PIP4K2A {ECO:0000312|HGNC:HGNC:8997};
GN Synonyms=PI5P4KA, PIP5K2, PIP5K2A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 30-42; 74-88;
RP 93-112; 141-145; 254-259; 281-297 AND 383-406, AND TISSUE SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=7852364; DOI=10.1074/jbc.270.7.2881;
RA Boronenkov I.V., Anderson R.A.;
RT "The sequence of phosphatidylinositol-4-phosphate 5-kinase defines a novel
RT family of lipid kinases.";
RL J. Biol. Chem. 270:2881-2884(1995).
RN [2]
RP SEQUENCE REVISION TO 298-310 AND 381-382.
RA Boronenkov I.V.;
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP SER-251.
RC TISSUE=Leukocyte;
RX PubMed=7639683; DOI=10.1042/bj3090715;
RA Divecha N., Truong O., Hsuan J.J., Hinchliffe K.A., Irvine R.F.;
RT "The cloning and sequence of the C isoform of PtdIns4P 5-kinase.";
RL Biochem. J. 309:715-719(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Hippocampus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=9367159; DOI=10.1038/36621;
RA Rameh L.E., Tolias K.F., Duckworth B.C., Cantley L.C.;
RT "A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.";
RL Nature 390:192-196(1997).
RN [10]
RP FUNCTION.
RX PubMed=18364242; DOI=10.1016/j.febslet.2008.03.022;
RA Wilcox A., Hinchliffe K.A.;
RT "Regulation of extranuclear PtdIns5P production by phosphatidylinositol
RT phosphate 4-kinase 2alpha.";
RL FEBS Lett. 582:1391-1394(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT THR-3 AND SER-14, CLEAVAGE OF INITIATOR METHIONINE [LARGE
RP SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-89 AND LYS-145, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [15]
RP BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION WITH PIP4K2B, SUBCELLULAR
RP LOCATION, MUTAGENESIS OF GLY-131 AND TYR-138, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=20583997; DOI=10.1042/bj20100341;
RA Bultsma Y., Keune W.-J., Divecha N.;
RT "PIP4Kbeta interacts with and modulates nuclear localization of the high-
RT activity PtdIns5P-4-kinase isoform PIP4Kalpha.";
RL Biochem. J. 430:223-235(2010).
RN [16]
RP REVIEW ON FUNCTION.
RX PubMed=19896968; DOI=10.1016/j.advenzreg.2009.10.006;
RA Clarke J.H., Wang M., Irvine R.F.;
RT "Localization, regulation and function of type II phosphatidylinositol 5-
RT phosphate 4-kinases.";
RL Adv. Enzyme Regul. 50:12-18(2010).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT SER-14, CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE
RP ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-3 AND SER-14, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [21]
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=23326584; DOI=10.1371/journal.pone.0054127;
RA Davis M.I., Sasaki A.T., Shen M., Emerling B.M., Thorne N., Michael S.,
RA Pragani R., Boxer M., Sumita K., Takeuchi K., Auld D.S., Li Z.,
RA Cantley L.C., Simeonov A.;
RT "A homogeneous, high-throughput assay for phosphatidylinositol 5-phosphate
RT 4-kinase with a novel, rapid substrate preparation.";
RL PLoS ONE 8:e54127-e54127(2013).
RN [22]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=26774281; DOI=10.1016/j.molcel.2015.12.011;
RA Sumita K., Lo Y.H., Takeuchi K., Senda M., Kofuji S., Ikeda Y.,
RA Terakawa J., Sasaki M., Yoshino H., Majd N., Zheng Y., Kahoud E.R.,
RA Yokota T., Emerling B.M., Asara J.M., Ishida T., Locasale J.W., Daikoku T.,
RA Anastasiou D., Senda T., Sasaki A.T.;
RT "The Lipid Kinase PI5P4Kbeta Is an Intracellular GTP Sensor for Metabolism
RT and Tumorigenesis.";
RL Mol. Cell 61:187-198(2016).
RN [23]
RP FUNCTION.
RX PubMed=31091439; DOI=10.1016/j.celrep.2019.04.070;
RA Wang D.G., Paddock M.N., Lundquist M.R., Sun J.Y., Mashadova O.,
RA Amadiume S., Bumpus T.W., Hodakoski C., Hopkins B.D., Fine M., Hill A.,
RA Yang T.J., Baskin J.M., Dow L.E., Cantley L.C.;
RT "PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent
RT Mechanism.";
RL Cell Rep. 27:1991.e5-2001.e5(2019).
RN [24]
RP CHARACTERIZATION OF VARIANT SER-251, AND MUTAGENESIS OF ASP-273.
RX PubMed=24081551; DOI=10.1007/s00213-013-3299-y;
RA Clarke J.H., Irvine R.F.;
RT "Enzyme activity of the PIP4K2A gene product polymorphism that is
RT implicated in schizophrenia.";
RL Psychopharmacology 230:329-331(2013).
RN [25]
RP FUNCTION, MUTAGENESIS OF ASP-273, AND CHARACTERIZATION OF VARIANT SER-251.
RX PubMed=29353240; DOI=10.1194/jlr.m082149;
RA Hu A., Zhao X.T., Tu H., Xiao T., Fu T., Wang Y., Liu Y., Shi X.J., Luo J.,
RA Song B.L.;
RT "PIP4K2A regulates intracellular cholesterol transport through modulating
RT PI(4,5)P2 homeostasis.";
RL J. Lipid Res. 59:507-514(2018).
RN [26] {ECO:0007744|PDB:6OSP}
RP X-RAY CRYSTALLOGRAPHY (2.21 ANGSTROMS) OF 35-405, AND SUBUNIT.
RX PubMed=32130941; DOI=10.1016/j.chembiol.2020.02.003;
RA Sivakumaren S.C., Shim H., Zhang T., Ferguson F.M., Lundquist M.R.,
RA Browne C.M., Seo H.S., Paddock M.N., Manz T.D., Jiang B., Hao M.F.,
RA Krishnan P., Wang D.G., Yang T.J., Kwiatkowski N.P., Ficarro S.B.,
RA Cunningham J.M., Marto J.A., Dhe-Paganon S., Cantley L.C., Gray N.S.;
RT "Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent
RT Inhibitors.";
RL Cell Chem. Biol. 27:525-537.e6(2020).
CC -!- FUNCTION: Catalyzes the phosphorylation of phosphatidylinositol 5-
CC phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring,
CC to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)
CC (PubMed:9367159, PubMed:23326584). Has both ATP- and GTP-dependent
CC kinase activities (PubMed:26774281). May exert its function by
CC regulating the levels of PtdIns5P, which functions in the cytosol by
CC increasing AKT activity and in the nucleus signals through ING2
CC (PubMed:18364242). May regulate the pool of cytosolic PtdIns5P in
CC response to the activation of tyrosine phosphorylation (By similarity).
CC Required for lysosome-peroxisome membrane contacts and intracellular
CC cholesterol transport through modulating peroxisomal PtdIns(4,5)P2
CC level (PubMed:29353240). In collaboration with PIP4K2B, has a role in
CC mediating autophagy in times of nutrient stress (By similarity).
CC Required for autophagosome-lysosome fusion and the regulation of
CC cellular lipid metabolism (PubMed:31091439). May be involved in
CC thrombopoiesis, and the terminal maturation of megakaryocytes and
CC regulation of their size (By similarity). Negatively regulates insulin
CC signaling through a catalytic-independent mechanism (PubMed:31091439).
CC PIP4Ks interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2
CC synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3
CC (PubMed:31091439). {ECO:0000250|UniProtKB:O70172,
CC ECO:0000250|UniProtKB:Q9R0I8, ECO:0000269|PubMed:18364242,
CC ECO:0000269|PubMed:23326584, ECO:0000269|PubMed:26774281,
CC ECO:0000269|PubMed:29353240, ECO:0000269|PubMed:31091439,
CC ECO:0000269|PubMed:9367159}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-
CC phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-4,5-bisphosphate) + ADP + H(+); Xref=Rhea:RHEA:12280,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57795,
CC ChEBI:CHEBI:58456, ChEBI:CHEBI:456216; EC=2.7.1.149;
CC Evidence={ECO:0000269|PubMed:9367159};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12281;
CC Evidence={ECO:0000305|PubMed:9367159};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-5-
CC phosphate) + ATP = 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-4,5-bisphosphate) + ADP + H(+); Xref=Rhea:RHEA:55992,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:83423,
CC ChEBI:CHEBI:84968, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:23326584, ECO:0000269|PubMed:26774281};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55993;
CC Evidence={ECO:0000305|PubMed:26774281};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-5-
CC phosphate) + GTP = 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-4,5-bisphosphate) + GDP + H(+); Xref=Rhea:RHEA:55964,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, ChEBI:CHEBI:58189,
CC ChEBI:CHEBI:83423, ChEBI:CHEBI:84968;
CC Evidence={ECO:0000269|PubMed:26774281};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55965;
CC Evidence={ECO:0000305|PubMed:26774281};
CC -!- ACTIVITY REGULATION: In rod outer segments, activated by light.
CC Inhibited by I-OMe tyrphostin AG-538 (I-OMe-AG-538), acting as an ATP-
CC competitive inhibitor (PubMed:23326584). {ECO:0000250|UniProtKB:Q9R0I8,
CC ECO:0000269|PubMed:23326584}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=50 uM for phosphatidylinositol-5- phosphate
CC {ECO:0000269|PubMed:20583997};
CC KM=5 uM for ATP {ECO:0000269|PubMed:26774281};
CC KM=3 uM for GTP {ECO:0000269|PubMed:26774281};
CC Vmax=466 pmol/min/ug enzyme {ECO:0000269|PubMed:20583997};
CC -!- SUBUNIT: Homodimer (PubMed:32130941). Interacts with PIP4K2B; the
CC interaction may regulate localization to the nucleus (PubMed:20583997).
CC Probably interacts with PIP5K1A; the interaction inhibits PIP5K1A
CC kinase activity (By similarity). {ECO:0000250|UniProtKB:Q8TBX8,
CC ECO:0000269|PubMed:20583997, ECO:0000269|PubMed:32130941}.
CC -!- INTERACTION:
CC P48426; Q99687-3: MEIS3; NbExp=3; IntAct=EBI-3924422, EBI-18582591;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O70172}.
CC Nucleus {ECO:0000269|PubMed:20583997}. Lysosome
CC {ECO:0000250|UniProtKB:O70172}. Cytoplasm
CC {ECO:0000269|PubMed:20583997}. Photoreceptor inner segment
CC {ECO:0000250|UniProtKB:O70172}. Cell projection, cilium, photoreceptor
CC outer segment {ECO:0000250|UniProtKB:O70172}. Note=May translocate from
CC the cytosol to the cell membrane upon activation of tyrosine
CC phosphorylation. May translocate from the inner to the outer segments
CC of the rod photoreceptor cells in response to light (By similarity).
CC Localization to the nucleus is modulated by the interaction with
CC PIP4K2B. {ECO:0000250|UniProtKB:O70172, ECO:0000269|PubMed:20583997}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P48426-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P48426-2; Sequence=VSP_056458;
CC -!- TISSUE SPECIFICITY: Expressed ubiquitously, with high levels in the
CC brain. Present in most tissues, except notably skeletal muscle and
CC small intestine. {ECO:0000269|PubMed:7639683,
CC ECO:0000269|PubMed:7852364}.
CC -!- PTM: Phosphorylated in tyrosines. Phosphorylation is induced by light
CC and increases kinase activity. {ECO:0000250|UniProtKB:Q9R0I8}.
CC -!- CAUTION: This protein was previously thought to be a
CC phosphatidylinositol 4-phosphate 5-kinase. {ECO:0000305}.
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DR EMBL; U14957; AAA64835.2; -; mRNA.
DR EMBL; S78798; AAB35041.1; -; mRNA.
DR EMBL; AL513128; CAH72211.1; -; Genomic_DNA.
DR EMBL; AL157707; CAH72211.1; JOINED; Genomic_DNA.
DR EMBL; AL390318; CAH72211.1; JOINED; Genomic_DNA.
DR EMBL; AK294817; BAG57933.1; -; mRNA.
DR EMBL; EF445009; ACA06044.1; -; Genomic_DNA.
DR EMBL; EF445009; ACA06045.1; -; Genomic_DNA.
DR EMBL; AL157707; CAI39585.1; -; Genomic_DNA.
DR EMBL; AL390318; CAI39585.1; JOINED; Genomic_DNA.
DR EMBL; AL513128; CAI39585.1; JOINED; Genomic_DNA.
DR EMBL; AL390318; CAH70526.1; -; Genomic_DNA.
DR EMBL; AL157707; CAH70526.1; JOINED; Genomic_DNA.
DR EMBL; AL513128; CAH70526.1; JOINED; Genomic_DNA.
DR EMBL; CH471072; EAW86140.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86141.1; -; Genomic_DNA.
DR EMBL; BC018034; AAH18034.1; -; mRNA.
DR CCDS; CCDS7141.1; -. [P48426-1]
DR CCDS; CCDS81443.1; -. [P48426-2]
DR PIR; A55967; A55967.
DR PIR; S57217; S57217.
DR RefSeq; NP_001316991.1; NM_001330062.1. [P48426-2]
DR RefSeq; NP_005019.2; NM_005028.4. [P48426-1]
DR RefSeq; XP_016871819.1; XM_017016330.1. [P48426-2]
DR RefSeq; XP_016871820.1; XM_017016331.1. [P48426-2]
DR PDB; 2YBX; X-ray; 2.56 A; A/B=35-405.
DR PDB; 6OSP; X-ray; 2.21 A; A/B=35-405.
DR PDB; 6UX9; X-ray; 1.71 A; A/B=35-405.
DR PDB; 6YM3; X-ray; 2.05 A; A/B=35-405.
DR PDB; 6YM4; X-ray; 1.95 A; A/B=35-405.
DR PDB; 6YM5; X-ray; 2.50 A; A/B=35-405.
DR PDB; 7N6Z; X-ray; 2.20 A; A=33-405.
DR PDB; 7N71; X-ray; 2.50 A; A=33-405.
DR PDB; 7N7J; X-ray; 2.10 A; A=33-405.
DR PDB; 7N7K; X-ray; 2.00 A; A=33-405.
DR PDB; 7N7L; X-ray; 2.70 A; A=33-405.
DR PDB; 7N7M; X-ray; 2.60 A; A=33-405.
DR PDB; 7N7N; X-ray; 2.30 A; A=33-405.
DR PDB; 7N7O; X-ray; 2.70 A; A=33-405.
DR PDBsum; 2YBX; -.
DR PDBsum; 6OSP; -.
DR PDBsum; 6UX9; -.
DR PDBsum; 6YM3; -.
DR PDBsum; 6YM4; -.
DR PDBsum; 6YM5; -.
DR PDBsum; 7N6Z; -.
DR PDBsum; 7N71; -.
DR PDBsum; 7N7J; -.
DR PDBsum; 7N7K; -.
DR PDBsum; 7N7L; -.
DR PDBsum; 7N7M; -.
DR PDBsum; 7N7N; -.
DR PDBsum; 7N7O; -.
DR AlphaFoldDB; P48426; -.
DR SMR; P48426; -.
DR BioGRID; 111322; 182.
DR IntAct; P48426; 105.
DR MINT; P48426; -.
DR STRING; 9606.ENSP00000365757; -.
DR BindingDB; P48426; -.
DR ChEMBL; CHEMBL1795194; -.
DR GuidetoPHARMACOLOGY; 2858; -.
DR SwissLipids; SLP:000000855; -.
DR iPTMnet; P48426; -.
DR PhosphoSitePlus; P48426; -.
DR BioMuta; PIP4K2A; -.
DR DMDM; 18266879; -.
DR OGP; P48426; -.
DR EPD; P48426; -.
DR jPOST; P48426; -.
DR MassIVE; P48426; -.
DR MaxQB; P48426; -.
DR PaxDb; P48426; -.
DR PeptideAtlas; P48426; -.
DR PRIDE; P48426; -.
DR ProteomicsDB; 4169; -.
DR ProteomicsDB; 55887; -. [P48426-1]
DR Antibodypedia; 25686; 367 antibodies from 33 providers.
DR DNASU; 5305; -.
DR Ensembl; ENST00000376573.9; ENSP00000365757.4; ENSG00000150867.14. [P48426-1]
DR Ensembl; ENST00000545335.5; ENSP00000442098.1; ENSG00000150867.14. [P48426-2]
DR GeneID; 5305; -.
DR KEGG; hsa:5305; -.
DR MANE-Select; ENST00000376573.9; ENSP00000365757.4; NM_005028.5; NP_005019.2.
DR UCSC; uc001irl.5; human. [P48426-1]
DR CTD; 5305; -.
DR DisGeNET; 5305; -.
DR GeneCards; PIP4K2A; -.
DR HGNC; HGNC:8997; PIP4K2A.
DR HPA; ENSG00000150867; Tissue enriched (brain).
DR MalaCards; PIP4K2A; -.
DR MIM; 603140; gene.
DR neXtProt; NX_P48426; -.
DR OpenTargets; ENSG00000150867; -.
DR Orphanet; 585877; B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality.
DR PharmGKB; PA162399615; -.
DR VEuPathDB; HostDB:ENSG00000150867; -.
DR eggNOG; KOG0229; Eukaryota.
DR GeneTree; ENSGT00940000156508; -.
DR HOGENOM; CLU_004312_7_0_1; -.
DR InParanoid; P48426; -.
DR OMA; LTRMHLM; -.
DR OrthoDB; 1562683at2759; -.
DR PhylomeDB; P48426; -.
DR TreeFam; TF354315; -.
DR BioCyc; MetaCyc:HS07693-MON; -.
DR BRENDA; 2.7.1.149; 2681.
DR PathwayCommons; P48426; -.
DR Reactome; R-HSA-1660499; Synthesis of PIPs at the plasma membrane.
DR Reactome; R-HSA-6811555; PI5P Regulates TP53 Acetylation.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-8847453; Synthesis of PIPs in the nucleus.
DR SABIO-RK; P48426; -.
DR SignaLink; P48426; -.
DR SIGNOR; P48426; -.
DR BioGRID-ORCS; 5305; 17 hits in 1085 CRISPR screens.
DR ChiTaRS; PIP4K2A; human.
DR GeneWiki; PIP4K2A; -.
DR GenomeRNAi; 5305; -.
DR Pharos; P48426; Tbio.
DR PRO; PR:P48426; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P48426; protein.
DR Bgee; ENSG00000150867; Expressed in inferior olivary complex and 197 other tissues.
DR ExpressionAtlas; P48426; baseline and differential.
DR Genevisible; P48426; HS.
DR GO; GO:0005776; C:autophagosome; IMP:ParkinsonsUK-UCL.
DR GO; GO:0005829; C:cytosol; IDA:FlyBase.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0001917; C:photoreceptor inner segment; IEA:UniProtKB-SubCell.
DR GO; GO:0001750; C:photoreceptor outer segment; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:FlyBase.
DR GO; GO:0016308; F:1-phosphatidylinositol-4-phosphate 5-kinase activity; IDA:UniProtKB.
DR GO; GO:0016309; F:1-phosphatidylinositol-5-phosphate 4-kinase activity; IDA:FlyBase.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:1902635; P:1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate biosynthetic process; IDA:UniProtKB.
DR GO; GO:0061909; P:autophagosome-lysosome fusion; ISS:UniProtKB.
DR GO; GO:0035855; P:megakaryocyte development; IEA:Ensembl.
DR GO; GO:0090217; P:negative regulation of 1-phosphatidylinositol-4-phosphate 5-kinase activity; IMP:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0046854; P:phosphatidylinositol phosphate biosynthetic process; IBA:GO_Central.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:2000786; P:positive regulation of autophagosome assembly; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010506; P:regulation of autophagy; IMP:ParkinsonsUK-UCL.
DR GO; GO:0090119; P:vesicle-mediated cholesterol transport; IMP:UniProtKB.
DR Gene3D; 3.30.800.10; -; 1.
DR InterPro; IPR023610; PInositol-4-P-5-kinase.
DR InterPro; IPR002498; PInositol-4-P-5-kinase_core.
DR InterPro; IPR027484; PInositol-4-P-5-kinase_N.
DR PANTHER; PTHR23086; PTHR23086; 1.
DR Pfam; PF01504; PIP5K; 1.
DR SMART; SM00330; PIPKc; 1.
DR PROSITE; PS51455; PIPK; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Cell membrane; Cell projection; Cytoplasm; Direct protein sequencing;
KW Kinase; Lipid metabolism; Lysosome; Membrane; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:22223895"
FT CHAIN 2..406
FT /note="Phosphatidylinositol 5-phosphate 4-kinase type-2
FT alpha"
FT /id="PRO_0000185465"
FT DOMAIN 33..405
FT /note="PIPK"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00781"
FT REGION 59..65
FT /note="Required for interaction with PIP5K1A"
FT /evidence="ECO:0000250|UniProtKB:Q8TBX8"
FT REGION 288..329
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 288..302
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:22223895"
FT MOD_RES 3
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 14
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 89
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 145
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 1..59
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056458"
FT VARIANT 7
FT /note="L -> I (in dbSNP:rs11813789)"
FT /id="VAR_059764"
FT VARIANT 251
FT /note="N -> S (no effect on kinase activity; increased
FT accumulation of lysosomal cholesterol; dbSNP:rs2230469)"
FT /evidence="ECO:0000269|PubMed:29353240,
FT ECO:0000269|PubMed:7639683"
FT /id="VAR_024565"
FT MUTAGEN 131
FT /note="G->L: Abolishes catalytic activity; when associated
FT with F-138."
FT /evidence="ECO:0000269|PubMed:20583997"
FT MUTAGEN 138
FT /note="Y->F: Abolishes catalytic activity; when associated
FT with L-131."
FT /evidence="ECO:0000269|PubMed:20583997"
FT MUTAGEN 273
FT /note="D->K: Loss of kinase activity. Increases
FT accumulation of lysosomal cholesterol."
FT /evidence="ECO:0000269|PubMed:29353240"
FT CONFLICT 101..103
FT /note="LRE -> CGK (in Ref. 3; AAB35041)"
FT /evidence="ECO:0000305"
FT CONFLICT 109
FT /note="D -> V (in Ref. 3; AAB35041)"
FT /evidence="ECO:0000305"
FT CONFLICT 143
FT /note="I -> M (in Ref. 3; AAB35041)"
FT /evidence="ECO:0000305"
FT CONFLICT 177..178
FT /note="QF -> HL (in Ref. 3; AAB35041)"
FT /evidence="ECO:0000305"
FT CONFLICT 333
FT /note="D -> E (in Ref. 3; AAB35041)"
FT /evidence="ECO:0000305"
FT HELIX 36..52
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 63..67
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 69..80
FT /evidence="ECO:0007829|PDB:6UX9"
FT TURN 81..83
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 86..94
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 95..104
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 109..117
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 122..124
FT /evidence="ECO:0007829|PDB:7N6Z"
FT STRAND 134..136
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 140..147
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 149..168
FT /evidence="ECO:0007829|PDB:6UX9"
FT TURN 169..171
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 178..186
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 189..197
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 202..204
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 207..212
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 215..217
FT /evidence="ECO:0007829|PDB:2YBX"
FT HELIX 223..227
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 228..230
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 232..234
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 235..240
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 249..268
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 271..273
FT /evidence="ECO:0007829|PDB:2YBX"
FT STRAND 275..282
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 283..287
FT /evidence="ECO:0007829|PDB:6UX9"
FT TURN 334..336
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 340..342
FT /evidence="ECO:0007829|PDB:6UX9"
FT STRAND 351..358
FT /evidence="ECO:0007829|PDB:6UX9"
FT HELIX 364..373
FT /evidence="ECO:0007829|PDB:7N7J"
FT HELIX 390..404
FT /evidence="ECO:0007829|PDB:6UX9"
SQ SEQUENCE 406 AA; 46225 MW; 5BAF0A27CC9EF376 CRC64;
MATPGNLGSS VLASKTKTKK KHFVAQKVKL FRASDPLLSV LMWGVNHSIN ELSHVQIPVM
LMPDDFKAYS KIKVDNHLFN KENMPSHFKF KEYCPMVFRN LRERFGIDDQ DFQNSLTRSA
PLPNDSQARS GARFHTSYDK RYIIKTITSE DVAEMHNILK KYHQYIVECH GITLLPQFLG
MYRLNVDGVE IYVIVTRNVF SHRLSVYRKY DLKGSTVARE ASDKEKAKEL PTLKDNDFIN
EGQKIYIDDN NKKVFLEKLK KDVEFLAQLK LMDYSLLVGI HDVERAEQEE VECEENDGEE
EGESDGTHPV GTPPDSPGNT LNSSPPLAPG EFDPNIDVYG IKCHENSPRK EVYFMAIIDI
LTHYDAKKKA AHAAKTVKHG AGAEISTVNP EQYSKRFLDF IGHILT
