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 27-MAR-2024, entry version 194. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 PDB; 8C8C; X-ray; 2.10 A; A=33-406. 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 PDBsum; 8C8C; -. DR AlphaFoldDB; P48426; -. DR SMR; P48426; -. DR BioGRID; 111322; 203. DR IntAct; P48426; 107. DR MINT; P48426; -. DR STRING; 9606.ENSP00000365757; -. DR BindingDB; P48426; -. DR ChEMBL; CHEMBL1795194; -. DR GuidetoPHARMACOLOGY; 2858; -. DR SwissLipids; SLP:000000855; -. DR GlyGen; P48426; 1 site, 1 O-linked glycan (1 site). 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; 9606-ENSP00000365757; -. DR PeptideAtlas; P48426; -. DR ProteomicsDB; 4169; -. DR ProteomicsDB; 55887; -. [P48426-1] DR Pumba; P48426; -. DR Antibodypedia; 25686; 406 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 AGR; HGNC:8997; -. DR CTD; 5305; -. DR DisGeNET; 5305; -. DR GeneCards; PIP4K2A; -. DR HGNC; HGNC:8997; PIP4K2A. DR HPA; ENSG00000150867; Tissue enhanced (brain). DR MalaCards; PIP4K2A; -. DR MIM; 603140; gene. DR neXtProt; NX_P48426; -. DR OpenTargets; ENSG00000150867; -. DR Orphanet; 585936; B-lymphoblastic leukemia/lymphoma with hyperdiploidy. 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; MFTREIT; -. DR OrthoDB; 5481504at2759; -. DR PhylomeDB; P48426; -. DR TreeFam; TF354315; -. DR BioCyc; MetaCyc:HS07693-MONOMER; -. 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; 19 hits in 1163 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 198 other cell types or tissues. DR ExpressionAtlas; P48426; baseline and differential. 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: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 CDD; cd17309; PIPKc_PIP5K2A; 1. DR Gene3D; 3.30.810.10; 2-Layer Sandwich; 2. DR Gene3D; 3.30.800.10; Phosphatidylinositol Phosphate Kinase II Beta; 1. DR InterPro; IPR027483; PInositol-4-P-4/5-kinase_C_sf. DR InterPro; IPR002498; PInositol-4-P-4/5-kinase_core. DR InterPro; IPR027484; PInositol-4-P-5-kinase_N. DR InterPro; IPR023610; PInositol-4/5-P-5/4-kinase. DR PANTHER; PTHR23086:SF21; PHOSPHATIDYLINOSITOL 5-PHOSPHATE 4-KINASE TYPE-2 ALPHA; 1. DR PANTHER; PTHR23086; PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE; 1. DR Pfam; PF01504; PIP5K; 1. DR SMART; SM00330; PIPKc; 1. DR SUPFAM; SSF56104; SAICAR synthase-like; 1. DR PROSITE; PS51455; PIPK; 1. DR Genevisible; P48426; HS. 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..366 FT /evidence="ECO:0007829|PDB:8C8C" 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 //