ID PLCG2_HUMAN Reviewed; 1265 AA. AC P16885; D3DUL3; Q3ZTS2; Q59H45; Q969T5; DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 4. DT 24-JAN-2024, entry version 248. DE RecName: Full=1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 {ECO:0000305}; DE EC=3.1.4.11 {ECO:0000269|PubMed:23000145}; DE AltName: Full=Phosphoinositide phospholipase C-gamma-2; DE AltName: Full=Phospholipase C-IV; DE Short=PLC-IV; DE AltName: Full=Phospholipase C-gamma-2; DE Short=PLC-gamma-2; GN Name=PLCG2 {ECO:0000312|HGNC:HGNC:9066}; 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]. RC TISSUE=Lymphoblast; RX PubMed=2849563; DOI=10.1016/0014-5793(88)80979-7; RA Ohta S., Matsui A., Nazawa Y., Kagawa Y.; RT "Complete cDNA encoding a putative phospholipase C from transformed human RT lymphocytes."; RL FEBS Lett. 242:31-35(1988). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Spleen; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=16533400; DOI=10.1186/1471-2164-7-48; RA Kemmer D., Podowski R.M., Arenillas D., Lim J., Hodges E., Roth P., RA Sonnhammer E.L.L., Hoeoeg C., Wasserman W.W.; RT "NovelFam3000 -- uncharacterized human protein domains conserved across RT model organisms."; RL BMC Genomics 7:48-48(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ARG-244 AND TYR-883. RC TISSUE=Lymph; 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 [7] RP PHOSPHORYLATION AT TYR-753 AND TYR-759. RX PubMed=11606584; DOI=10.1074/jbc.m107577200; RA Rodriguez R., Matsuda M., Perisic O., Bravo J., Paul A., Jones N.P., RA Light Y., Swann K., Williams R.L., Katan M.; RT "Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme RT function in B-cell signaling."; RL J. Biol. Chem. 276:47982-47992(2001). RN [8] RP PHOSPHORYLATION AT TYR-753 AND TYR-759. RX PubMed=12181444; DOI=10.1124/mol.62.3.672; RA Ozdener F., Dangelmaier C., Ashby B., Kunapuli S.P., Daniel J.L.; RT "Activation of phospholipase Cgamma2 by tyrosine phosphorylation."; RL Mol. Pharmacol. 62:672-679(2002). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1245, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=15144186; DOI=10.1021/ac035352d; RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., RA Peters E.C.; RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from RT human T cells using immobilized metal affinity chromatography and tandem RT mass spectrometry."; RL Anal. Chem. 76:2763-2772(2004). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-753; TYR-759 AND TYR-1217, RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [11] 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 [12] RP IDENTIFICATION IN A COMPLEX WITH EEIG1; TNFRSF11A; GAB2; TEC AND BTK. RX PubMed=23478294; DOI=10.1038/cr.2013.33; RA Choi H.K., Kang H.R., Jung E., Kim T.E., Lin J.J., Lee S.Y.; RT "Early estrogen-induced gene 1, a novel RANK signaling component, is RT essential for osteoclastogenesis."; RL Cell Res. 23:524-536(2013). RN [13] RP INVOLVEMENT IN FCAS3. RX PubMed=22236196; DOI=10.1056/nejmoa1102140; RA Ombrello M.J., Remmers E.F., Sun G., Freeman A.F., Datta S., RA Torabi-Parizi P., Subramanian N., Bunney T.D., Baxendale R.W., RA Martins M.S., Romberg N., Komarow H., Aksentijevich I., Kim H.S., Ho J., RA Cruse G., Jung M.Y., Gilfillan A.M., Metcalfe D.D., Nelson C., O'Brien M., RA Wisch L., Stone K., Douek D.C., Gandhi C., Wanderer A.A., Lee H., RA Nelson S.F., Shianna K.V., Cirulli E.T., Goldstein D.B., Long E.O., RA Moir S., Meffre E., Holland S.M., Kastner D.L., Katan M., Hoffman H.M., RA Milner J.D.; RT "Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 RT deletions."; RL N. Engl. J. Med. 366:330-338(2012). RN [14] RP VARIANT APLAID TYR-707, CATALYTIC ACTIVITY, FUNCTION, AND CHARACTERIZATION RP OF VARIANT APLAID TYR-707. RX PubMed=23000145; DOI=10.1016/j.ajhg.2012.08.006; RA Zhou Q., Lee G.S., Brady J., Datta S., Katan M., Sheikh A., Martins M.S., RA Bunney T.D., Santich B.H., Moir S., Kuhns D.B., Long Priel D.A., RA Ombrello A., Stone D., Ombrello M.J., Khan J., Milner J.D., Kastner D.L., RA Aksentijevich I.; RT "A hypermorphic missense mutation in PLCG2, encoding phospholipase Cgamma2, RT causes a dominantly inherited autoinflammatory disease with RT immunodeficiency."; RL Am. J. Hum. Genet. 91:713-720(2012). RN [15] RP VARIANTS TRP-665 AND PHE-845. RX PubMed=24869598; DOI=10.1056/nejmoa1400029; RA Woyach J.A., Furman R.R., Liu T.M., Ozer H.G., Zapatka M., Ruppert A.S., RA Xue L., Li D.H., Steggerda S.M., Versele M., Dave S.S., Zhang J., RA Yilmaz A.S., Jaglowski S.M., Blum K.A., Lozanski A., Lozanski G., RA James D.F., Barrientos J.C., Lichter P., Stilgenbauer S., Buggy J.J., RA Chang B.Y., Johnson A.J., Byrd J.C.; RT "Resistance mechanisms for the Bruton's tyrosine kinase inhibitor RT ibrutinib."; RL N. Engl. J. Med. 370:2286-2294(2014). CC -!- FUNCTION: The production of the second messenger molecules CC diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated CC by activated phosphatidylinositol-specific phospholipase C enzymes. It CC is a crucial enzyme in transmembrane signaling. CC {ECO:0000269|PubMed:23000145}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5- CC bisphosphate) + H2O = 1D-myo-inositol 1,4,5-trisphosphate + a 1,2- CC diacyl-sn-glycerol + H(+); Xref=Rhea:RHEA:33179, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17815, ChEBI:CHEBI:58456, CC ChEBI:CHEBI:203600; EC=3.1.4.11; CC Evidence={ECO:0000269|PubMed:23000145}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33180; CC Evidence={ECO:0000305|PubMed:23000145}; CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; CC -!- SUBUNIT: Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, CC GAB2, TEC and BTK; complex formation increases in the presence of CC TNFSF11/RANKL (PubMed:23478294). Interacts (via SH2 domain) with CSF1R CC (tyrosine phosphorylated). Interacts constitutively with THEMIS2. CC {ECO:0000250|UniProtKB:Q8CIH5, ECO:0000269|PubMed:23478294}. CC -!- INTERACTION: CC P16885; P10275: AR; NbExp=6; IntAct=EBI-617403, EBI-608057; CC P16885; P00533: EGFR; NbExp=6; IntAct=EBI-617403, EBI-297353; CC P16885; P19235: EPOR; NbExp=3; IntAct=EBI-617403, EBI-617321; CC P16885; P04626: ERBB2; NbExp=3; IntAct=EBI-617403, EBI-641062; CC P16885; O95073-2: FSBP; NbExp=2; IntAct=EBI-617403, EBI-10696047; CC P16885; Q13480: GAB1; NbExp=15; IntAct=EBI-617403, EBI-517684; CC P16885; P10721: KIT; NbExp=8; IntAct=EBI-617403, EBI-1379503; CC P16885; O43242: PSMD3; NbExp=2; IntAct=EBI-617403, EBI-357622; CC P16885; O14796: SH2D1B; NbExp=2; IntAct=EBI-617403, EBI-3923013; CC -!- SUBCELLULAR LOCATION: Membrane raft {ECO:0000250|UniProtKB:Q8CIH5}. CC -!- PTM: Phosphorylated on tyrosine residues by CSF1R (By similarity). CC Phosphorylated on tyrosine residues by BTK and SYK; upon ligand-induced CC activation of a variety of growth factor receptors and immune system CC receptors. Phosphorylation leads to increased phospholipase activity. CC {ECO:0000250|UniProtKB:Q8CIH5, ECO:0000269|PubMed:11606584, CC ECO:0000269|PubMed:12181444}. CC -!- DISEASE: Familial cold autoinflammatory syndrome 3 (FCAS3) CC [MIM:614468]: An autosomal dominant immune disorder characterized by CC the development of cutaneous urticaria, erythema, and pruritis in CC response to cold exposure. Affected individuals have variable CC additional immunologic defects, including antibody deficiency, CC decreased numbers of B-cells, defective B-cells, increased CC susceptibility to infection, and increased risk of autoimmune CC disorders. {ECO:0000269|PubMed:22236196}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Autoinflammation, antibody deficiency, and immune CC dysregulation (APLAID) [MIM:614878]: An autosomal dominant systemic CC disorder characterized by recurrent blistering skin lesions with a CC dense inflammatory infiltrate and variable involvement of other CC tissues, including joints, the eye, and the gastrointestinal tract. CC Affected individuals have a mild humoral immune deficiency associated CC with recurrent sinopulmonary infections, but no evidence of circulating CC autoantibodies. {ECO:0000269|PubMed:23000145}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=AAA60112.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAQ76815.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAD92151.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=CAA32194.1; Type=Frameshift; Evidence={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; M37238; AAA60112.1; ALT_FRAME; mRNA. DR EMBL; X14034; CAA32194.1; ALT_FRAME; mRNA. DR EMBL; AB208914; BAD92151.1; ALT_INIT; mRNA. DR EMBL; AY364256; AAQ76815.1; ALT_FRAME; mRNA. DR EMBL; AC092142; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC098966; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC099524; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471114; EAW95524.1; -; Genomic_DNA. DR EMBL; CH471114; EAW95525.1; -; Genomic_DNA. DR EMBL; BC007565; AAH07565.1; -; mRNA. DR EMBL; BC011772; AAH11772.1; -; mRNA. DR EMBL; BC014561; AAH14561.1; -; mRNA. DR EMBL; BC018646; AAH18646.1; -; mRNA. DR CCDS; CCDS42204.1; -. DR PIR; S02004; S02004. DR RefSeq; NP_002652.2; NM_002661.4. DR PDB; 2K2J; NMR; -; A=471-514, A=841-913. DR PDB; 2W2W; X-ray; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L=471-514, A/B/C/D/E/F/G/H/I/J/K/L=841-913. DR PDB; 2W2X; X-ray; 2.30 A; C/D=471-514, C/D=841-913. DR PDBsum; 2K2J; -. DR PDBsum; 2W2W; -. DR PDBsum; 2W2X; -. DR AlphaFoldDB; P16885; -. DR BMRB; P16885; -. DR SMR; P16885; -. DR BioGRID; 111352; 74. DR CORUM; P16885; -. DR IntAct; P16885; 69. DR MINT; P16885; -. DR STRING; 9606.ENSP00000482457; -. DR BindingDB; P16885; -. DR ChEMBL; CHEMBL4100; -. DR GuidetoPHARMACOLOGY; 1408; -. DR SwissLipids; SLP:000000647; -. DR MoonDB; P16885; Predicted. DR GlyGen; P16885; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P16885; -. DR PhosphoSitePlus; P16885; -. DR BioMuta; PLCG2; -. DR DMDM; 215274231; -. DR EPD; P16885; -. DR jPOST; P16885; -. DR MassIVE; P16885; -. DR MaxQB; P16885; -. DR PaxDb; 9606-ENSP00000482457; -. DR PeptideAtlas; P16885; -. DR ProteomicsDB; 53400; -. DR Pumba; P16885; -. DR Antibodypedia; 3797; 1157 antibodies from 43 providers. DR DNASU; 5336; -. DR Ensembl; ENST00000564138.6; ENSP00000482457.1; ENSG00000197943.12. DR GeneID; 5336; -. DR KEGG; hsa:5336; -. DR MANE-Select; ENST00000564138.6; ENSP00000482457.1; NM_002661.5; NP_002652.2. DR UCSC; uc002fgt.4; human. DR AGR; HGNC:9066; -. DR CTD; 5336; -. DR DisGeNET; 5336; -. DR GeneCards; PLCG2; -. DR HGNC; HGNC:9066; PLCG2. DR HPA; ENSG00000197943; Tissue enhanced (lymphoid). DR MalaCards; PLCG2; -. DR MIM; 600220; gene. DR MIM; 614468; phenotype. DR MIM; 614878; phenotype. DR neXtProt; NX_P16885; -. DR OpenTargets; ENSG00000197943; -. DR Orphanet; 324530; Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation. DR Orphanet; 300359; PLCG2-associated antibody deficiency and immune dysregulation. DR PharmGKB; PA33393; -. DR VEuPathDB; HostDB:ENSG00000197943; -. DR eggNOG; KOG1264; Eukaryota. DR GeneTree; ENSGT00940000157517; -. DR HOGENOM; CLU_002738_5_1_1; -. DR InParanoid; P16885; -. DR OMA; EDPPVEF; -. DR OrthoDB; 2900494at2759; -. DR PhylomeDB; P16885; -. DR TreeFam; TF313216; -. DR BioCyc; MetaCyc:HS06773-MONOMER; -. DR BRENDA; 3.1.4.11; 2681. DR PathwayCommons; P16885; -. DR Reactome; R-HSA-114604; GPVI-mediated activation cascade. DR Reactome; R-HSA-166016; Toll Like Receptor 4 (TLR4) Cascade. DR Reactome; R-HSA-1855204; Synthesis of IP3 and IP4 in the cytosol. DR Reactome; R-HSA-202433; Generation of second messenger molecules. DR Reactome; R-HSA-2029485; Role of phospholipids in phagocytosis. DR Reactome; R-HSA-2424491; DAP12 signaling. DR Reactome; R-HSA-2871796; FCERI mediated MAPK activation. DR Reactome; R-HSA-2871809; FCERI mediated Ca+2 mobilization. DR Reactome; R-HSA-5607764; CLEC7A (Dectin-1) signaling. DR Reactome; R-HSA-5621480; Dectin-2 family. DR Reactome; R-HSA-9027277; Erythropoietin activates Phospholipase C gamma (PLCG). DR Reactome; R-HSA-9664323; FCGR3A-mediated IL10 synthesis. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9680350; Signaling by CSF1 (M-CSF) in myeloid cells. DR Reactome; R-HSA-983695; Antigen activates B Cell Receptor (BCR) leading to generation of second messengers. DR SignaLink; P16885; -. DR SIGNOR; P16885; -. DR BioGRID-ORCS; 5336; 15 hits in 1164 CRISPR screens. DR ChiTaRS; PLCG2; human. DR EvolutionaryTrace; P16885; -. DR GeneWiki; PLCG2; -. DR GenomeRNAi; 5336; -. DR Pharos; P16885; Tchem. DR PRO; PR:P16885; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; P16885; Protein. DR Bgee; ENSG00000197943; Expressed in renal glomerulus and 161 other cell types or tissues. DR ExpressionAtlas; P16885; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:ARUK-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0097708; C:intracellular vesicle; IDA:ARUK-UCL. DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ARUK-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0032587; C:ruffle membrane; IDA:ARUK-UCL. DR GO; GO:0004435; F:phosphatidylinositol phospholipase C activity; IDA:UniProtKB. DR GO; GO:0004629; F:phospholipase C activity; TAS:Reactome. DR GO; GO:0140031; F:phosphorylation-dependent protein binding; IEA:Ensembl. DR GO; GO:0001784; F:phosphotyrosine residue binding; IPI:CAFA. DR GO; GO:0019901; F:protein kinase binding; IPI:ARUK-UCL. DR GO; GO:1990782; F:protein tyrosine kinase binding; IPI:ARUK-UCL. DR GO; GO:0097110; F:scaffold protein binding; IPI:ARUK-UCL. DR GO; GO:0061760; P:antifungal innate immune response; ISS:ARUK-UCL. DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB. DR GO; GO:0050853; P:B cell receptor signaling pathway; IDA:ARUK-UCL. DR GO; GO:0019722; P:calcium-mediated signaling; IMP:ARUK-UCL. DR GO; GO:0001775; P:cell activation; ISS:ARUK-UCL. DR GO; GO:0071277; P:cellular response to calcium ion; IMP:ARUK-UCL. DR GO; GO:1990858; P:cellular response to lectin; ISS:ARUK-UCL. DR GO; GO:0071396; P:cellular response to lipid; IMP:ARUK-UCL. DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome. DR GO; GO:0002316; P:follicular B cell differentiation; IEA:Ensembl. DR GO; GO:0032959; P:inositol trisphosphate biosynthetic process; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ARUK-UCL. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IMP:ARUK-UCL. DR GO; GO:0002281; P:macrophage activation involved in immune response; ISS:ARUK-UCL. DR GO; GO:0043069; P:negative regulation of programmed cell death; IEA:Ensembl. DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; IDA:UniProtKB. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IBA:GO_Central. DR GO; GO:0009395; P:phospholipid catabolic process; IEA:InterPro. DR GO; GO:0030168; P:platelet activation; TAS:Reactome. DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; ISS:ARUK-UCL. DR GO; GO:1902808; P:positive regulation of cell cycle G1/S phase transition; ISS:ARUK-UCL. DR GO; GO:0002732; P:positive regulation of dendritic cell cytokine production; ISS:ARUK-UCL. DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISS:ARUK-UCL. DR GO; GO:0010634; P:positive regulation of epithelial cell migration; IBA:GO_Central. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:1903721; P:positive regulation of I-kappaB phosphorylation; ISS:ARUK-UCL. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; ISS:ARUK-UCL. DR GO; GO:0032735; P:positive regulation of interleukin-12 production; ISS:ARUK-UCL. DR GO; GO:0032743; P:positive regulation of interleukin-2 production; ISS:ARUK-UCL. DR GO; GO:0032747; P:positive regulation of interleukin-23 production; ISS:ARUK-UCL. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:ARUK-UCL. DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; ISS:ARUK-UCL. DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:ARUK-UCL. DR GO; GO:0150078; P:positive regulation of neuroinflammatory response; IMP:ARUK-UCL. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:ARUK-UCL. DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; IMP:ARUK-UCL. DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISS:ARUK-UCL. DR GO; GO:0060100; P:positive regulation of phagocytosis, engulfment; IMP:ARUK-UCL. DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; ISS:ARUK-UCL. DR GO; GO:0002092; P:positive regulation of receptor internalization; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:ARUK-UCL. DR GO; GO:0032481; P:positive regulation of type I interferon production; IEA:Ensembl. DR GO; GO:0012501; P:programmed cell death; IEA:Ensembl. DR GO; GO:0070884; P:regulation of calcineurin-NFAT signaling cascade; ISS:ARUK-UCL. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; ISS:ARUK-UCL. DR GO; GO:0019216; P:regulation of lipid metabolic process; IMP:ARUK-UCL. DR GO; GO:0051209; P:release of sequestered calcium ion into cytosol; IDA:UniProtKB. DR GO; GO:0048678; P:response to axon injury; IMP:ARUK-UCL. DR GO; GO:0001878; P:response to yeast; ISS:ARUK-UCL. DR GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; ISS:ARUK-UCL. DR GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0002224; P:toll-like receptor signaling pathway; ISS:ARUK-UCL. DR GO; GO:0016055; P:Wnt signaling pathway; TAS:UniProtKB. DR CDD; cd00275; C2_PLC_like; 1. DR CDD; cd16215; EFh_PI-PLCgamma2; 1. DR CDD; cd13362; PH_PLC_gamma; 1. DR CDD; cd13234; PHsplit_PLC_gamma; 1. DR CDD; cd08592; PI-PLCc_gamma; 1. DR CDD; cd09932; SH2_C-SH2_PLC_gamma_like; 1. DR CDD; cd10341; SH2_N-SH2_PLC_gamma_like; 1. DR CDD; cd11969; SH3_PLCgamma2; 1. DR Gene3D; 2.60.40.150; C2 domain; 1. DR Gene3D; 3.20.20.190; Phosphatidylinositol (PI) phosphodiesterase; 2. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1. DR Gene3D; 3.30.505.10; SH2 domain; 2. DR Gene3D; 2.30.30.40; SH3 Domains; 1. DR InterPro; IPR000008; C2_dom. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR011992; EF-hand-dom_pair. DR InterPro; IPR011993; PH-like_dom_sf. DR InterPro; IPR001849; PH_domain. DR InterPro; IPR001192; PI-PLC_fam. DR InterPro; IPR016279; PLC-gamma. DR InterPro; IPR035023; PLC-gamma_C-SH2. DR InterPro; IPR035024; PLC-gamma_N-SH2. DR InterPro; IPR017946; PLC-like_Pdiesterase_TIM-brl. DR InterPro; IPR035723; PLCgamma2_SH3. DR InterPro; IPR000909; PLipase_C_PInositol-sp_X_dom. DR InterPro; IPR001711; PLipase_C_Pinositol-sp_Y. DR InterPro; IPR000980; SH2. DR InterPro; IPR036860; SH2_dom_sf. DR InterPro; IPR036028; SH3-like_dom_sf. DR InterPro; IPR001452; SH3_domain. DR PANTHER; PTHR10336:SF25; 1-PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE PHOSPHODIESTERASE GAMMA-2; 1. DR PANTHER; PTHR10336; PHOSPHOINOSITIDE-SPECIFIC PHOSPHOLIPASE C FAMILY PROTEIN; 1. DR Pfam; PF00168; C2; 1. DR Pfam; PF16457; PH_12; 1. DR Pfam; PF00388; PI-PLC-X; 1. DR Pfam; PF00387; PI-PLC-Y; 1. DR Pfam; PF00017; SH2; 2. DR Pfam; PF00018; SH3_1; 1. DR PIRSF; PIRSF000952; PLC-gamma; 1. DR PRINTS; PR00390; PHPHLIPASEC. DR PRINTS; PR00401; SH2DOMAIN. DR PRINTS; PR00452; SH3DOMAIN. DR SMART; SM00239; C2; 1. DR SMART; SM00233; PH; 2. DR SMART; SM00148; PLCXc; 1. DR SMART; SM00149; PLCYc; 1. DR SMART; SM00252; SH2; 2. DR SMART; SM00326; SH3; 1. DR SUPFAM; SSF49562; C2 domain (Calcium/lipid-binding domain, CaLB); 1. DR SUPFAM; SSF47473; EF-hand; 1. DR SUPFAM; SSF50729; PH domain-like; 1. DR SUPFAM; SSF51695; PLC-like phosphodiesterases; 1. DR SUPFAM; SSF55550; SH2 domain; 2. DR SUPFAM; SSF50044; SH3-domain; 1. DR PROSITE; PS50004; C2; 1. DR PROSITE; PS50003; PH_DOMAIN; 1. DR PROSITE; PS50007; PIPLC_X_DOMAIN; 1. DR PROSITE; PS50008; PIPLC_Y_DOMAIN; 1. DR PROSITE; PS50001; SH2; 2. DR PROSITE; PS50002; SH3; 1. DR Genevisible; P16885; HS. PE 1: Evidence at protein level; KW 3D-structure; Calcium; Disease variant; Hydrolase; Lipid degradation; KW Lipid metabolism; Membrane; Phosphoprotein; Reference proteome; Repeat; KW SH2 domain; SH3 domain; Transducer. FT CHAIN 1..1265 FT /note="1-phosphatidylinositol 4,5-bisphosphate FT phosphodiesterase gamma-2" FT /id="PRO_0000088501" FT DOMAIN 20..131 FT /note="PH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145" FT DOMAIN 312..456 FT /note="PI-PLC X-box" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00270" FT DOMAIN 532..635 FT /note="SH2 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191" FT DOMAIN 646..735 FT /note="SH2 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191" FT DOMAIN 769..829 FT /note="SH3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192" FT DOMAIN 930..1044 FT /note="PI-PLC Y-box" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00271" FT DOMAIN 1038..1169 FT /note="C2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT ACT_SITE 327 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00270" FT ACT_SITE 372 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00270" FT MOD_RES 753 FT /note="Phosphotyrosine; by BTK" FT /evidence="ECO:0000269|PubMed:11606584, FT ECO:0000269|PubMed:12181444, ECO:0007744|PubMed:19690332" FT MOD_RES 759 FT /note="Phosphotyrosine; by BTK" FT /evidence="ECO:0000269|PubMed:11606584, FT ECO:0000269|PubMed:12181444, ECO:0007744|PubMed:19690332" FT MOD_RES 1197 FT /note="Phosphotyrosine; by BTK" FT /evidence="ECO:0000250|UniProtKB:P24135" FT MOD_RES 1217 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 1245 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15144186" FT VARIANT 244 FT /note="H -> R (in dbSNP:rs11548656)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_031560" FT VARIANT 268 FT /note="R -> W (in dbSNP:rs1143687)" FT /id="VAR_031561" FT VARIANT 541 FT /note="T -> A (in dbSNP:rs11548657)" FT /id="VAR_047427" FT VARIANT 665 FT /note="R -> W (found in patients with chronic lymphocytic FT leukemia; uncertain significance; results in resistance to FT ibrutinib therapy; dbSNP:rs1057519831)" FT /evidence="ECO:0000269|PubMed:24869598" FT /id="VAR_074310" FT VARIANT 707 FT /note="S -> Y (in APLAID; results in increased epidermal FT growth factor-stimulated production of intracellular IP3 FT and increased intracellular calcium release; is a FT hypermorphic mutation; dbSNP:rs397514562)" FT /evidence="ECO:0000269|PubMed:23000145" FT /id="VAR_069211" FT VARIANT 845 FT /note="L -> F (found in patients with chronic lymphocytic FT leukemia; uncertain significance; results in resistance to FT ibrutinib therapy; dbSNP:rs1057519832)" FT /evidence="ECO:0000269|PubMed:24869598" FT /id="VAR_074311" FT VARIANT 883 FT /note="D -> Y (in dbSNP:rs17856213)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_047428" FT CONFLICT 606..610 FT /note="TFSSI -> RFRRM (in Ref. 1; CAA32194/AAA60112 and 3; FT AAQ76815)" FT /evidence="ECO:0000305" FT CONFLICT 623 FT /note="R -> P (in Ref. 1; AAA60112/CAA32194 and 3; FT AAQ76815)" FT /evidence="ECO:0000305" FT CONFLICT 745 FT /note="M -> T (in Ref. 1; AAA60112/CAA32194 and 3; FT AAQ76815)" FT /evidence="ECO:0000305" FT CONFLICT 880 FT /note="Q -> E (in Ref. 1; AAA60112/CAA32194 and 3; FT AAQ76815)" FT /evidence="ECO:0000305" FT CONFLICT 912 FT /note="T -> S (in Ref. 1; AAA60112/CAA32194 and 3; FT AAQ76815)" FT /evidence="ECO:0000305" FT CONFLICT 1095 FT /note="D -> G (in Ref. 1; AAA60112/CAA32194 and 3; FT AAQ76815)" FT /evidence="ECO:0000305" FT TURN 815..817 FT /evidence="ECO:0007829|PDB:2W2X" FT STRAND 818..825 FT /evidence="ECO:0007829|PDB:2W2X" FT STRAND 828..831 FT /evidence="ECO:0007829|PDB:2W2X" FT HELIX 835..840 FT /evidence="ECO:0007829|PDB:2W2X" FT STRAND 850..854 FT /evidence="ECO:0007829|PDB:2W2X" FT HELIX 855..857 FT /evidence="ECO:0007829|PDB:2W2X" FT STRAND 858..862 FT /evidence="ECO:0007829|PDB:2W2X" FT STRAND 867..869 FT /evidence="ECO:0007829|PDB:2K2J" FT STRAND 870..882 FT /evidence="ECO:0007829|PDB:2W2X" FT STRAND 886..892 FT /evidence="ECO:0007829|PDB:2W2X" FT HELIX 893..907 FT /evidence="ECO:0007829|PDB:2W2X" SQ SEQUENCE 1265 AA; 147870 MW; 1D56BCBF51D7A0D3 CRC64; MSTTVNVDSL AEYEKSQIKR ALELGTVMTV FSFRKSTPER RTVQVIMETR QVAWSKTADK IEGFLDIMEI KEIRPGKNSK DFERAKAVRQ KEDCCFTILY GTQFVLSTLS LAADSKEDAV NWLSGLKILH QEAMNASTPT IIESWLRKQI YSVDQTRRNS ISLRELKTIL PLINFKVSSA KFLKDKFVEI GAHKDELSFE QFHLFYKKLM FEQQKSILDE FKKDSSVFIL GNTDRPDASA VYLHDFQRFL IHEQQEHWAQ DLNKVRERMT KFIDDTMRET AEPFLFVDEF LTYLFSRENS IWDEKYDAVD MQDMNNPLSH YWISSSHNTY LTGDQLRSES SPEAYIRCLR MGCRCIELDC WDGPDGKPVI YHGWTRTTKI KFDDVVQAIK DHAFVTSSFP VILSIEEHCS VEQQRHMAKA FKEVFGDLLL TKPTEASADQ LPSPSQLREK IIIKHKKLGP RGDVDVNMED KKDEHKQQGE LYMWDSIDQK WTRHYCAIAD AKLSFSDDIE QTMEEEVPQD IPPTELHFGE KWFHKKVEKR TSAEKLLQEY CMETGGKDGT FLVRESETFP NDYTLSFWRS GRVQHCRIRS TMEGGTLKYY LTDNLTFSSI YALIQHYRET HLRCAEFELR LTDPVPNPNP HESKPWYYDS LSRGEAEDML MRIPRDGAFL IRKREGSDSY AITFRARGKV KHCRINRDGR HFVLGTSAYF ESLVELVSYY EKHSLYRKMR LRYPVTPELL ERYNMERDIN SLYDVSRMYV DPSEINPSMP QRTVKALYDY KAKRSDELSF CRGALIHNVS KEPGGWWKGD YGTRIQQYFP SNYVEDISTA DFEELEKQII EDNPLGSLCR GILDLNTYNV VKAPQGKNQK SFVFILEPKQ QGDPPVEFAT DRVEELFEWF QSIREITWKI DTKENNMKYW EKNQSIAIEL SDLVVYCKPT SKTKDNLENP DFREIRSFVE TKADSIIRQK PVDLLKYNQK GLTRVYPKGQ RVDSSNYDPF RLWLCGSQMV ALNFQTADKY MQMNHALFSL NGRTGYVLQP ESMRTEKYDP MPPESQRKIL MTLTVKVLGA RHLPKLGRSI ACPFVEVEIC GAEYDNNKFK TTVVNDNGLS PIWAPTQEKV TFEIYDPNLA FLRFVVYEED MFSDPNFLAH ATYPIKAVKS GFRSVPLKNG YSEDIELASL LVFCEMRPVL ESEEELYSSC RQLRRRQEEL NNQLFLYDTH QNLRNANRDA LVKEFSVNEN QLQLYQEKCN KRLREKRVSN SKFYS //