ID PK3CB_HUMAN Reviewed; 1070 AA. AC P42338; D3DNF0; Q24JU2; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 1. DT 25-JAN-2012, entry version 112. DE RecName: Full=Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform; DE Short=PI3-kinase subunit beta; DE Short=PI3K-beta; DE Short=PI3Kbeta; DE Short=PtdIns-3-kinase subunit beta; DE EC=2.7.1.153; DE AltName: Full=Phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit beta; DE Short=PtdIns-3-kinase subunit p110-beta; DE Short=p110beta; GN Name=PIK3CB; Synonyms=PIK3C1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX MEDLINE=94067128; PubMed=8246984; RA Hu P., Mondino A., Skolnik E.Y., Schlessinger J.; RT "Cloning of a novel, ubiquitously expressed human phosphatidylinositol RT 3-kinase and identification of its binding site on p85."; RL Mol. Cell. Biol. 13:7677-7688(1993). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11016459; RA Kossila M., Sinkovic M., Karkkainen P., Laukkanen M.O., Miettinen R., RA Rissanen J., Kekalainen P., Kuusisto J., Yla-Herttuala S., Laakso M.; RT "Gene encoding the catalytic subunit p110beta of human RT phosphatidylinositol 3-kinase: cloning, genomic structure, and RT screening for variants in patients with type 2 diabetes."; RL Diabetes 49:1740-1743(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP AUTOPHOSPHORYLATION AT SER-1070. RX PubMed=12502714; DOI=10.1074/jbc.M210351200; RA Czupalla C., Culo M., Muller E.C., Brock C., Reusch H.P., Spicher K., RA Krause E., Nurnberg B.; RT "Identification and characterization of the autophosphorylation sites RT of phosphoinositide 3-kinase isoforms beta and gamma."; RL J. Biol. Chem. 278:11536-11545(2003). RN [6] RP FUNCTION, AND MUTAGENESIS OF LYS-805. RX PubMed=18594509; DOI=10.1038/nature07091; RA Jia S., Liu Z., Zhang S., Liu P., Zhang L., Lee S.H., Zhang J., RA Signoretti S., Loda M., Roberts T.M., Zhao J.J.; RT "Essential roles of PI(3)K-p110beta in cell growth, metabolism and RT tumorigenesis."; RL Nature 454:776-779(2008). RN [7] RP FUNCTION IN ONCOGENIC SIGNALING. RX PubMed=18755892; DOI=10.1073/pnas.0802655105; RA Wee S., Wiederschain D., Maira S.-M., Loo A., Miller C., RA deBeaumont R., Stegmeier F., Yao Y.-M., Lengauer C.; RT "PTEN-deficient cancers depend on PIK3CB."; RL Proc. Natl. Acad. Sci. U.S.A. 105:13057-13062(2008). RN [8] RP IDENTIFICATION IN A COMPLEX WITH PIK3R1 AND PTEN. RX PubMed=19635806; DOI=10.1128/MCB.01649-08; RA Rabinovsky R., Pochanard P., McNear C., Brachmann S.M., RA Duke-Cohan J.S., Garraway L.A., Sellers W.R.; RT "p85 Associates with unphosphorylated PTEN and the PTEN-associated RT complex."; RL Mol. Cell. Biol. 29:5377-5388(2009). RN [9] RP FUNCTION, AND MUTAGENESIS OF LYS-342. RX PubMed=21030680; DOI=10.1073/pnas.1008739107; RA Dbouk H.A., Pang H., Fiser A., Backer J.M.; RT "A biochemical mechanism for the oncogenic potential of the p110beta RT catalytic subunit of phosphoinositide 3-kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 107:19897-19902(2010). RN [10] RP FUNCTION, INTERACTION WITH PIK3R2, SUBCELLULAR LOCATION, AND MOTIF RP NLS. RX PubMed=21383062; DOI=10.1128/MCB.01313-10; RA Kumar A., Redondo-Munoz J., Perez-Garcia V., Cortes I., Chagoyen M., RA Carrera A.C.; RT "Nuclear but not cytosolic phosphoinositide 3-kinase beta has an RT essential function in cell survival."; RL Mol. Cell. Biol. 31:2122-2133(2011). RN [11] RP REVIEW ON FUNCTION. RX PubMed=21321382; RA Dbouk H.A., Backer J.M.; RT "A beta version of life: p110beta takes center stage."; RL Oncotarget 1:729-733(2010). RN [12] RP REVIEW ON FUNCTION. RX PubMed=21035500; DOI=10.1016/j.advenzreg.2010.09.011; RA Gratacap M.-P., Guillermet-Guibert J., Martin V., Chicanne G., RA Tronchere H., Gaits-Iacovoni F., Payrastre B.; RT "Regulation and roles of PI3Kbeta, a major actor in platelet signaling RT and functions."; RL Adv. Enzyme Regul. 51:106-116(2011). RN [13] 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., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). CC -!- FUNCTION: Phosphoinositide-3-kinase (PI3K) that phosphorylates CC PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- CC phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- CC bisphosphate) to generate phosphatidylinositol-3,4,5-triphosphate CC (PIP3). PIP3 plays a key role by recruiting PH domain-containing CC proteins to the membrane, including AKT1 and PDPK1, activating CC signaling cascades involved in cell growth, survival, CC proliferation, motility and morphology. Involved in the activation CC of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) CC ligands such as CXCL12, sphingosine 1-phosphate, and CC lysophosphatidic acid. May also act downstream receptor tyrosine CC kinases. Required in different signaling pathways for stable CC platelet adhesion and aggregation. Plays a role in platelet CC activation signaling triggered by GPCRs, alpha-IIb/beta-3 CC integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based CC activation motif)-bearing receptors such as GP6. Regulates the CC strength of adhesion of ITGA2B/ ITGB3 activated receptors CC necessary for the cellular transmission of contractile forces. CC Required for platelet aggregation induced by F2 (thrombin) and CC thromboxane A2 (TXA2). Has a role in cell survival. May have a CC role in cell migration. Involved in the early stage of CC autophagosome formation. Modulates the intracellular level of CC PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 CC kinase activity. May act as a scaffold, independently of its lipid CC kinase activity to positively regulate autophagy. May have a role CC in insulin signaling as scaffolding protein in which the lipid CC kinase activity is not required. May have a kinase-independent CC function in regulating cell proliferation and in clathrin-mediated CC endocytosis. Mediator of oncogenic signal in cell lines lacking CC PTEN. The lipid kinase activity is necessary for its role in CC oncogenic transformation. Required for the growth of ERBB2 and RAS CC driven tumors. CC -!- CATALYTIC ACTIVITY: ATP + 1-phosphatidyl-1D-myo-inositol 4,5- CC bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5- CC trisphosphate. CC -!- PATHWAY: Phospholipid metabolism; phosphatidylinositol phosphate CC biosynthesis. CC -!- SUBUNIT: Heterodimer of a catalytic subunit PIK3CB and a p85 CC regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interaction with CC PIK3R2 is required for nuclear localization and nuclear export. CC Part of a complex with PIK3R1 and PTEN. Binding to PTEN may CC antagonize the lipid kinase activity under normal growth CC conditions. Part of a complex involved in autophagosome formation CC composed of PIK3C3 and PIK3R4 (By similarity). Interacts with CC BECN1, ATG14 and RAB5A (By similarity). CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Interaction with CC PIK3R2 is required for nuclear localization and export. CC -!- TISSUE SPECIFICITY: Expressed ubiquitously. CC -!- DOMAIN: The inhibitory interactions with PIK3R1 are mediated by CC the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 CC (inter-SH2) region of PIK3R1; the C2 PI3K-type domain, the PI3K CC helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N- CC terminal SH2) region of PIK3R1; and the PI3K/PI4K kinase domain CC with the cSH2 (C-terminal SH2) region of PIK3R1. The inhibitory CC interaction between the PI3K-ABD domain and the C2 PI3K-type CC domain with the iSH2 (inter-SH2) region of PIK3R1 is weak. The CC nuclear localization signal (NLS) is required for its function in CC cell survival. CC -!- PTM: Phosphorylation at Ser-1070 downregulates lipid kinase CC activity. CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. CC -!- SIMILARITY: Contains 1 C2 PI3K-type domain. CC -!- SIMILARITY: Contains 1 PI3K-ABD domain. CC -!- SIMILARITY: Contains 1 PI3K-RBD domain. CC -!- SIMILARITY: Contains 1 PI3K/PI4K domain. CC -!- SIMILARITY: Contains 1 PIK helical domain. CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; S67334; AAB29081.1; -; mRNA. DR EMBL; AJ297549; CAC21449.1; -; Genomic_DNA. DR EMBL; AJ297550; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297551; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297552; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297553; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297554; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297555; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297556; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297557; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297558; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297559; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; AJ297560; CAC21449.1; JOINED; Genomic_DNA. DR EMBL; CH471052; EAW79053.1; -; Genomic_DNA. DR EMBL; CH471052; EAW79055.1; -; Genomic_DNA. DR EMBL; BC114432; AAI14433.1; -; mRNA. DR IPI; IPI00031388; -. DR PIR; A54600; A54600. DR RefSeq; NP_006210.1; NM_006219.1. DR UniGene; Hs.239818; -. DR ProteinModelPortal; P42338; -. DR SMR; P42338; 533-1069. DR IntAct; P42338; 4. DR STRING; P42338; -. DR PhosphoSite; P42338; -. DR DMDM; 1171955; -. DR PeptideAtlas; P42338; -. DR PRIDE; P42338; -. DR Ensembl; ENST00000289153; ENSP00000289153; ENSG00000051382. DR Ensembl; ENST00000477593; ENSP00000418143; ENSG00000051382. DR GeneID; 5291; -. DR KEGG; hsa:5291; -. DR UCSC; uc003esu.1; human. DR CTD; 5291; -. DR GeneCards; GC03M138372; -. DR H-InvDB; HIX0030788; -. DR HGNC; HGNC:8976; PIK3CB. DR HPA; CAB031938; -. DR MIM; 602925; gene. DR neXtProt; NX_P42338; -. DR PharmGKB; PA33309; -. DR eggNOG; prNOG04282; -. DR HOGENOM; HBG445499; -. DR HOVERGEN; HBG052721; -. DR InParanoid; P42338; -. DR OMA; FQIVLVK; -. DR OrthoDB; EOG4ZPDTJ; -. DR PhylomeDB; P42338; -. DR BioCyc; MetaCyc:ENSG00000051382-MONOMER; -. DR Pathway_Interaction_DB; pi3kcipathway; Class I PI3K signaling events. DR Pathway_Interaction_DB; lysophospholipid_pathway; LPA receptor mediated events. DR Pathway_Interaction_DB; trail_pathway; TRAIL signaling pathway. DR Reactome; REACT_111102; Signal Transduction. DR Reactome; REACT_111155; Cell-Cell communication. DR Reactome; REACT_604; Hemostasis. DR Reactome; REACT_6900; Immune System. DR NextBio; 20446; -. DR ArrayExpress; P42338; -. DR Bgee; P42338; -. DR CleanEx; HS_PIK3CB; -. DR Genevestigator; P42338; -. DR GermOnline; ENSG00000051382; Homo sapiens. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; IEA:InterPro. DR GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; TAS:ProtInc. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; TAS:Reactome. DR GO; GO:0000187; P:activation of MAPK activity; TAS:ProtInc. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0006935; P:chemotaxis; TAS:ProtInc. DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; TAS:ProtInc. DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome. DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome. DR GO; GO:0048011; P:nerve growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome. DR GO; GO:0030168; P:platelet activation; TAS:Reactome. DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR008973; C2_Ca/lipid-bd_dom_CaLB. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR000403; PI3/4_kinase_cat. DR InterPro; IPR018936; PI3/4_kinase_CS. DR InterPro; IPR002420; PI3K_C2. DR InterPro; IPR003113; PI3K_p85-bd. DR InterPro; IPR000341; PI3K_ras-bd. DR InterPro; IPR015433; PI_Kinase. DR InterPro; IPR001263; PInositide-3_kin_accessory_dom. DR Gene3D; G3DSA:1.10.1070.11; PI3/4_kinase_cat; 1. DR Gene3D; G3DSA:1.25.40.70; PI3Ka; 1. DR KO; K00922; -. DR PANTHER; PTHR10048; PI_Kinase; 1. DR Pfam; PF00454; PI3_PI4_kinase; 1. DR Pfam; PF00792; PI3K_C2; 1. DR Pfam; PF02192; PI3K_p85B; 1. DR Pfam; PF00794; PI3K_rbd; 1. DR Pfam; PF00613; PI3Ka; 1. DR SMART; SM00142; PI3K_C2; 1. DR SMART; SM00143; PI3K_p85B; 1. DR SMART; SM00144; PI3K_rbd; 1. DR SMART; SM00145; PI3Ka; 1. DR SMART; SM00146; PI3Kc; 1. DR SUPFAM; SSF48371; ARM-type_fold; 1. DR SUPFAM; SSF49562; C2_CaLB; 1. DR SUPFAM; SSF56112; Kinase_like; 1. DR PROSITE; PS00915; PI3_4_KINASE_1; 1. DR PROSITE; PS00916; PI3_4_KINASE_2; 1. DR PROSITE; PS50290; PI3_4_KINASE_3; 1. DR PROSITE; PS51544; PI3K_ABD; 1. DR PROSITE; PS51547; PI3K_C2; 1. DR PROSITE; PS51546; PI3K_RBD; 1. DR PROSITE; PS51545; PIK_HELICAL; 1. PE 1: Evidence at protein level; KW ATP-binding; Autophagy; Cell adhesion; Complete proteome; Cytoplasm; KW Endocytosis; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; KW Polymorphism; Reference proteome; Transferase. FT CHAIN 1 1070 Phosphatidylinositol-4,5-bisphosphate 3- FT kinase catalytic subunit beta isoform. FT /FTId=PRO_0000088787. FT DOMAIN 26 115 PI3K-ABD. FT DOMAIN 194 285 PI3K-RBD. FT DOMAIN 327 496 C2 PI3K-type. FT DOMAIN 524 701 PIK helical. FT DOMAIN 800 1067 PI3K/PI4K. FT MOTIF 410 418 Nuclear localization signal. FT MOD_RES 1070 1070 Phosphoserine; by autocatalysis. FT VARIANT 672 672 Q -> H (in dbSNP:rs2230462). FT /FTId=VAR_050530. FT MUTAGEN 342 342 K->N: Enhanced inhibition by PIK3R1 FT leading to reduced lipid kinase activity FT and reduced oncogenicity. Does not modify FT regulation by GPCRs. FT MUTAGEN 805 805 K->R: Loss of lipid kinase activity. May FT not affect insulin signaling and cell FT proliferation. Partially affects FT oncogene-induced trasformation. SQ SEQUENCE 1070 AA; 122762 MW; 81135FE93452C00E CRC64; MCFSFIMPPA MADILDIWAV DSQIASDGSI PVDFLLPTGI YIQLEVPREA TISYIKQMLW KQVHNYPMFN LLMDIDSYMF ACVNQTAVYE ELEDETRRLC DVRPFLPVLK LVTRSCDPGE KLDSKIGVLI GKGLHEFDSL KDPEVNEFRR KMRKFSEEKI LSLVGLSWMD WLKQTYPPEH EPSIPENLED KLYGGKLIVA VHFENCQDVF SFQVSPNMNP IKVNELAIQK RLTIHGKEDE VSPYDYVLQV SGRVEYVFGD HPLIQFQYIR NCVMNRALPH FILVECCKIK KMYEQEMIAI EAAINRNSSN LPLPLPPKKT RIISHVWENN NPFQIVLVKG NKLNTEETVK VHVRAGLFHG TELLCKTIVS SEVSGKNDHI WNEPLEFDIN ICDLPRMARL CFAVYAVLDK VKTKKSTKTI NPSKYQTIRK AGKVHYPVAW VNTMVFDFKG QLRTGDIILH SWSSFPDELE EMLNPMGTVQ TNPYTENATA LHVKFPENKK QPYYYPPFDK IIEKAAEIAS SDSANVSSRG GKKFLPVLKE ILDRDPLSQL CENEMDLIWT LRQDCREIFP QSLPKLLLSI KWNKLEDVAQ LQALLQIWPK LPPREALELL DFNYPDQYVR EYAVGCLRQM SDEELSQYLL QLVQVLKYEP FLDCALSRFL LERALGNRRI GQFLFWHLRS EVHIPAVSVQ FGVILEAYCR GSVGHMKVLS KQVEALNKLK TLNSLIKLNA VKLNRAKGKE AMHTCLKQSA YREALSDLQS PLNPCVILSE LYVEKCKYMD SKMKPLWLVY NNKVFGEDSV GVIFKNGDDL RQDMLTLQML RLMDLLWKEA GLDLRMLPYG CLATGDRSGL IEVVSTSETI ADIQLNSSNV AAAAAFNKDA LLNWLKEYNS GDDLDRAIEE FTLSCAGYCV ASYVLGIGDR HSDNIMVKKT GQLFHIDFGH ILGNFKSKFG IKRERVPFIL TYDFIHVIQQ GKTGNTEKFG RFRQCCEDAY LILRRHGNLF ITLFALMLTA GLPELTSVKD IQYLKDSLAL GKSEEEALKQ FKQKFDEALR ESWTTKVNWM AHTVRKDYRS //