Full text data of PIK3CB
PIK3CB
(PIK3C1)
[Confidence: low (only semi-automatic identification from reviews)]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform; PI3-kinase subunit beta; PI3K-beta; PI3Kbeta; PtdIns-3-kinase subunit beta; 2.7.1.153 (Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit beta; PtdIns-3-kinase subunit p110-beta; p110beta)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform; PI3-kinase subunit beta; PI3K-beta; PI3Kbeta; PtdIns-3-kinase subunit beta; 2.7.1.153 (Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit beta; PtdIns-3-kinase subunit p110-beta; p110beta)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P42338
ID PK3CB_HUMAN Reviewed; 1070 AA.
AC P42338; D3DNF0; Q24JU2;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 133.
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 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; DOI=10.2337/diabetes.49.10.1740;
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 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).
RN [11]
RP FUNCTION, INTERACTION WITH PIK3R2, SUBCELLULAR LOCATION, AND MOTIF
RP NUCLEAR LOCALIZATION SIGNAL.
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 [12]
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 [13]
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).
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-trisphosphate
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 -!- INTERACTION:
CC P08631:HCK; NbExp=2; IntAct=EBI-2609540, EBI-346340;
CC O00459:PIK3R2; NbExp=3; IntAct=EBI-2609540, EBI-346930;
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 down-regulates 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.
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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 PIR; A54600; A54600.
DR RefSeq; NP_006210.1; NM_006219.2.
DR RefSeq; XP_005247587.1; XM_005247530.1.
DR RefSeq; XP_005247588.1; XM_005247531.1.
DR UniGene; Hs.239818; -.
DR ProteinModelPortal; P42338; -.
DR DIP; DIP-44775N; -.
DR IntAct; P42338; 13.
DR MINT; MINT-1505441; -.
DR STRING; 9606.ENSP00000289153; -.
DR BindingDB; P42338; -.
DR ChEMBL; CHEMBL3145; -.
DR GuidetoPHARMACOLOGY; 2154; -.
DR PhosphoSite; P42338; -.
DR DMDM; 1171955; -.
DR PaxDb; P42338; -.
DR PeptideAtlas; P42338; -.
DR PRIDE; P42338; -.
DR DNASU; 5291; -.
DR Ensembl; ENST00000289153; ENSP00000289153; ENSG00000051382.
DR Ensembl; ENST00000477593; ENSP00000418143; ENSG00000051382.
DR GeneID; 5291; -.
DR KEGG; hsa:5291; -.
DR UCSC; uc011bmq.3; human.
DR CTD; 5291; -.
DR GeneCards; GC03M138372; -.
DR HGNC; HGNC:8976; PIK3CB.
DR HPA; CAB031938; -.
DR MIM; 602925; gene.
DR neXtProt; NX_P42338; -.
DR PharmGKB; PA33309; -.
DR eggNOG; COG5032; -.
DR HOGENOM; HOG000252911; -.
DR HOVERGEN; HBG052721; -.
DR InParanoid; P42338; -.
DR KO; K00922; -.
DR OMA; AMHTCLK; -.
DR OrthoDB; EOG70CR65; -.
DR PhylomeDB; P42338; -.
DR BioCyc; MetaCyc:HS00644-MONOMER; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P42338; -.
DR UniPathway; UPA00220; -.
DR GeneWiki; PIK3CB; -.
DR GenomeRNAi; 5291; -.
DR NextBio; 20446; -.
DR PRO; PR:P42338; -.
DR ArrayExpress; P42338; -.
DR Bgee; P42338; -.
DR CleanEx; HS_PIK3CB; -.
DR Genevestigator; P42338; -.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; IBA:RefGenome.
DR GO; GO:0005886; C:plasma membrane; IBA:RefGenome.
DR GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; IBA:RefGenome.
DR GO; GO:0035005; F:1-phosphatidylinositol-4-phosphate 3-kinase activity; IBA:RefGenome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; IBA:RefGenome.
DR GO; GO:0000187; P:activation of MAPK activity; TAS:ProtInc.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0006935; P:chemotaxis; TAS:ProtInc.
DR GO; GO:0040016; P:embryonic cleavage; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
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:UniProtKB.
DR GO; GO:0007156; P:homophilic cell adhesion; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
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:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0014065; P:phosphatidylinositol 3-kinase cascade; TAS:UniProtKB.
DR GO; GO:0070527; P:platelet aggregation; TAS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; TAS:UniProtKB.
DR GO; GO:0001952; P:regulation of cell-matrix adhesion; IEA:Ensembl.
DR GO; GO:2000369; P:regulation of clathrin-mediated endocytosis; TAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.1070.11; -; 1.
DR Gene3D; 1.25.40.70; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR003113; PI3K_adapt-bd_dom.
DR InterPro; IPR002420; PI3K_C2_dom.
DR InterPro; IPR000341; PI3K_Ras-bd_dom.
DR InterPro; IPR015433; PI_Kinase.
DR InterPro; IPR001263; PInositide-3_kin_accessory_dom.
DR PANTHER; PTHR10048; PTHR10048; 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; SSF48371; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF56112; SSF56112; 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
//
ID PK3CB_HUMAN Reviewed; 1070 AA.
AC P42338; D3DNF0; Q24JU2;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 133.
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 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; DOI=10.2337/diabetes.49.10.1740;
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 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).
RN [11]
RP FUNCTION, INTERACTION WITH PIK3R2, SUBCELLULAR LOCATION, AND MOTIF
RP NUCLEAR LOCALIZATION SIGNAL.
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 [12]
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 [13]
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).
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-trisphosphate
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 -!- INTERACTION:
CC P08631:HCK; NbExp=2; IntAct=EBI-2609540, EBI-346340;
CC O00459:PIK3R2; NbExp=3; IntAct=EBI-2609540, EBI-346930;
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 down-regulates 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.
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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 PIR; A54600; A54600.
DR RefSeq; NP_006210.1; NM_006219.2.
DR RefSeq; XP_005247587.1; XM_005247530.1.
DR RefSeq; XP_005247588.1; XM_005247531.1.
DR UniGene; Hs.239818; -.
DR ProteinModelPortal; P42338; -.
DR DIP; DIP-44775N; -.
DR IntAct; P42338; 13.
DR MINT; MINT-1505441; -.
DR STRING; 9606.ENSP00000289153; -.
DR BindingDB; P42338; -.
DR ChEMBL; CHEMBL3145; -.
DR GuidetoPHARMACOLOGY; 2154; -.
DR PhosphoSite; P42338; -.
DR DMDM; 1171955; -.
DR PaxDb; P42338; -.
DR PeptideAtlas; P42338; -.
DR PRIDE; P42338; -.
DR DNASU; 5291; -.
DR Ensembl; ENST00000289153; ENSP00000289153; ENSG00000051382.
DR Ensembl; ENST00000477593; ENSP00000418143; ENSG00000051382.
DR GeneID; 5291; -.
DR KEGG; hsa:5291; -.
DR UCSC; uc011bmq.3; human.
DR CTD; 5291; -.
DR GeneCards; GC03M138372; -.
DR HGNC; HGNC:8976; PIK3CB.
DR HPA; CAB031938; -.
DR MIM; 602925; gene.
DR neXtProt; NX_P42338; -.
DR PharmGKB; PA33309; -.
DR eggNOG; COG5032; -.
DR HOGENOM; HOG000252911; -.
DR HOVERGEN; HBG052721; -.
DR InParanoid; P42338; -.
DR KO; K00922; -.
DR OMA; AMHTCLK; -.
DR OrthoDB; EOG70CR65; -.
DR PhylomeDB; P42338; -.
DR BioCyc; MetaCyc:HS00644-MONOMER; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P42338; -.
DR UniPathway; UPA00220; -.
DR GeneWiki; PIK3CB; -.
DR GenomeRNAi; 5291; -.
DR NextBio; 20446; -.
DR PRO; PR:P42338; -.
DR ArrayExpress; P42338; -.
DR Bgee; P42338; -.
DR CleanEx; HS_PIK3CB; -.
DR Genevestigator; P42338; -.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; IBA:RefGenome.
DR GO; GO:0005886; C:plasma membrane; IBA:RefGenome.
DR GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; IBA:RefGenome.
DR GO; GO:0035005; F:1-phosphatidylinositol-4-phosphate 3-kinase activity; IBA:RefGenome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; IBA:RefGenome.
DR GO; GO:0000187; P:activation of MAPK activity; TAS:ProtInc.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0006935; P:chemotaxis; TAS:ProtInc.
DR GO; GO:0040016; P:embryonic cleavage; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
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:UniProtKB.
DR GO; GO:0007156; P:homophilic cell adhesion; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
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:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0014065; P:phosphatidylinositol 3-kinase cascade; TAS:UniProtKB.
DR GO; GO:0070527; P:platelet aggregation; TAS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; TAS:UniProtKB.
DR GO; GO:0001952; P:regulation of cell-matrix adhesion; IEA:Ensembl.
DR GO; GO:2000369; P:regulation of clathrin-mediated endocytosis; TAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.1070.11; -; 1.
DR Gene3D; 1.25.40.70; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR003113; PI3K_adapt-bd_dom.
DR InterPro; IPR002420; PI3K_C2_dom.
DR InterPro; IPR000341; PI3K_Ras-bd_dom.
DR InterPro; IPR015433; PI_Kinase.
DR InterPro; IPR001263; PInositide-3_kin_accessory_dom.
DR PANTHER; PTHR10048; PTHR10048; 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; SSF48371; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF56112; SSF56112; 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
//
MIM
602925
*RECORD*
*FIELD* NO
602925
*FIELD* TI
*602925 PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, BETA; PIK3CB
;;PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, 110-KD, BETA;;
read morep110-BETA;;
PI3KCB;;
PI3K-BETA;;
PIK3-BETA
*FIELD* TX
DESCRIPTION
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position
of the inositol ring of inositol lipids. They have been implicated as
participants in signaling pathways regulating cell growth by virtue of
their activation in response to various mitogenic stimuli. PI3Ks are
composed of a 110-kD catalytic subunit, such as PIK3CB, and an 85-kD
adaptor subunit (Hu et al., 1993).
CLONING
To identify human genes encoding the PI3K catalytic subunit, Hu et al.
(1993) carried out RT-PCR with RNA from a T-lymphocyte cell line and
degenerate primers based on regions conserved between a bovine and a
yeast PI3K. The authors recovered a partial cDNA encoding a human PI3K
and used it to isolate additional cDNAs from an embryonic kidney cell
line (293) library. The predicted 1,070-amino acid protein, called
p110-beta by them, is 42% identical to that of bovine p110. Northern
blot analysis revealed that the major 4.8-kb p110-beta transcript was
expressed in several human and rodent cell lines, as well as in all
mouse tissues tested. Minor larger transcripts were detected in some
tissues and cell lines.
GENE FUNCTION
Using 293 cells expressing epitope tagged p110-beta, Hu et al. (1993)
demonstrated that the protein has PI3K activity. Antibodies against
p110-beta immunoprecipitated an endogenous PI3K activity from 293 cell
lysates. Both the epitope-tagged protein and endogenous p110-beta
associated with the 85-kD subunit in vivo.
Using flow-based adhesion assays with mouse and human platelets, Jackson
et al. (2005) determined that p110-beta has a role in regulating the
formation and stability of alpha-2B (ITGA2B; 607759)-beta-3 (ITGB3;
173470) integrin adhesion bonds, which are necessary for shear
force-induced platelet activation. p100-beta sustained alpha-2B-beta-3
integrin activation and stabilized platelet aggregation by regulating
both integrin-dependent calcium flux and Gi (see GNAI1; 139310)
activation of RAP1B (179530).
GENE STRUCTURE
Kossila et al. (2000) determined that the PIK3CB gene contains 22 exons
that are 51 to 252 basepairs in length.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PIK3CB
gene to chromosome 3 (TMAP WI-14619).
MOLECULAR GENETICS
Downregulation of the IGF1 (147440) pathway or IGF1 plasma levels is
associated with an increased life span. Bonafe et al. (2003) tested the
hypothesis that polymorphic variants of genes in the IGF1 response
pathway, namely IGF1R (147370) (G/A, codon 1013), PI3KCB (T/C, -359 bp;
A/G, -303 bp), IRS1 (147545) (G/A, codon 972), and FOXO1A (136533) (T/C,
+97347 bp), play a role in systemic IGF1 regulation and human longevity.
The major finding of this investigation was that subjects carrying at
least an A allele at IGF1R had low levels of free plasma IGF1 and were
more represented among long-lived people. Moreover, genotype
combinations at IGF1R and PIK3CB genes affect free IGF1 plasma levels
and longevity. Genotype combinations of an A allele at the IGF1R locus
and a T allele at the PI3CKB locus (A+/T+ subjects) affected IGF1 plasma
levels (with A-/T- individuals having the highest free IGF1 plasma
levels), as well as longevity, and the proportion of A+/T+ subjects
significantly increased among long-lived individuals.
Liu et al. (2008) explored a wide-range genetic basis for the
involvement of genetic alterations in receptor tyrosine kinases (RTKs)
and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in
anaplastic thyroid cancer (ATC) and follicular thyroid cancer (FTC;
188470). They found frequent copy gains of RTK genes including EGFR
(131550), and VEGFR1 (165070), and PIK3CA (171834) and PIK3CB in the
P13K/Akt pathway. Copy number gain of PIK3CB was found in 16 of 42 ATCs
(38%) and 25 of 55 FTCs (46%). RTK gene copy gains were preferentially
associated with phosphorylation of Akt, suggesting their dominant role
in activating the P13K/Akt pathway. Liu et al. (2008) concluded that
genetic alterations in the RTKs and P13K/Akt and MAPK pathways are
extremely prevalent in ATC and FTC, providing a strong genetic basis for
an extensive role of these signaling pathways and the development of
therapies targeting these pathways for ATC and FTC, particularly the
former.
Le Stunff et al. (2008) studied the p110-beta gene as a candidate gene
for association with insulin resistance (IR) and fasting glycemia in
severely obese children. They found that a SNP (dbSNP rs361072) located
in the promoter of the p110-beta gene was associated with fasting
glucose (P = 0.0002), insulin (P = 2.6 x 10(-8)), and homeostasis model
assessment insulin resistance index (P = 1 x 10(-9)) in severely obese
children. The effect of dbSNP rs361072 was marginal or not significant
in nonobese children. Le Stunff et al. (2008) concluded that the C
allele of dbSNP rs361072 attenuates IR in superobese children.
ANIMAL MODEL
To investigate distinct functions of p110-beta, Jia et al. (2008)
constructed conditional knockout mice. Ablation of p110-beta in the
livers of the resulting mice led to impaired insulin sensitivity and
glucose homeostasis, while having little effect on phosphorylation of
Akt (164730), suggesting the involvement of a kinase-independent role of
p110-beta in insulin metabolic action. Using established mouse embryonic
fibroblasts, Jia et al. (2008) found that removal of p110-beta also had
little effect on Akt phosphorylation in response to stimulation by
insulin and epidermal growth factor, but resulted in retarded cell
proliferation. Reconstitution of p110-beta-null cells with a wildtype or
kinase-dead allele of p110-beta demonstrated that p110-beta possesses
kinase-independent functions in regulating cell proliferation and
trafficking. However, the kinase activity of p110-beta was required for
G protein-coupled receptor signaling triggered by lysophosphatidic acid
and had a function in oncogenic transformation. Most strikingly, in an
animal model of prostate tumor formation induced by Pten (601728) loss,
ablation of p110-beta, but not that of p110-alpha (171834), impeded
tumorigenesis with a concomitant diminution of Akt phosphorylation. Jia
et al. (2008) concluded that, taken together, their findings
demonstrated both kinase-dependent and kinase-independent functions for
p110-beta.
Ciraolo et al. (2010) developed a line of mice expressing catalytically
inactive Pic3cb. Homozygous mutant mice were born and reached adulthood,
but while homozygous mutant females were fully fertile, homozygous
mutant males were subfertile. Mutant testis was reduced in size compared
with wildtype and immunohistochemical analysis revealed few spermatozoa
and hypocellular seminiferous tubules. Plasma testosterone was normal,
and FSH (see 136530) was elevated, suggesting primary gonadic failure in
mutant mice. Spermatogenic stem cell populations were observed, but they
were progressively lost, suggesting that inactivation of Pic3cb results
in a defect in spermatogenesis at later developmental stages. Kit
(164920)-positive cells were lost in adult mutant testis, and
pharmacologic inhibition of wildtype Pic3cb confirmed that Pic3cb is
downstream of Kit activation.
*FIELD* RF
1. Bonafe, M.; Barbieri, M.; Marchegiani, F.; Olivieri, F.; Ragno,
E.; Giampieri, C.; Mugianesi, E.; Centurelli, M.; Franceschi, C. and
Paolisso, G.: Polymorphic variants of insulin-like growth factor
I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I
plasma levels and human longevity: cues for an evolutionarily conserved
mechanism of life span control. J. Clin. Endocr. Metab. 88: 3299-3304,
2003.
2. Ciraolo, E.; Morello, F.; Hobbs, R. M.; Wolf, F.; Marone, R.; Iezzi,
M.; Lu, X.; Mengozzi, G.; Altruda, F.; Sorba, G.; Guan, K.; Pandolfi,
P. P.; Wymann, M. P.; Hirsch, E.: Essential role of the p110-beta
subunit of phosphoinositide 3-OH kinase in male fertility. Molec.
Biol. Cell 21: 704-711, 2010.
3. Hu, P.; Mondino, A.; Skolnik, E. Y.; Schlessinger, J.: Cloning
of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase
and identification of its binding site on p85. Molec. Cell. Biol. 13:
7677-7688, 1993.
4. Jackson, S. P.; Schoenwaelder, S. M.; Goncalves, I.; Nesbitt, W.
S.; Yap, C. L.; Wright, C. E.; Kenche, V.; Anderson, K. E.; Dopheide,
S. M.; Yuan, Y.; Sturgeon, S. A.; Prabaharan, H.; and 14 others
: PI 3-kinase p110-beta: a new target for antithrombotic therapy. Nature
Med. 11: 507-514, 2005.
5. Jia, S.; Liu, Z.; Zhang, S.; Liu, P.; Zhang, L.; Lee, S. H.; Zhang,
J.; Signoretti, S.; Loda, M.; Roberts, T. M.; Zhao, J. J.: Essential
roles of PI(3)K-p110-beta in cell growth, metabolism and tumorigenesis. Nature 454:
776-779, 2008.
6. Kossila, M.; Sinkovic, M.; Karkkainen, P.; Laukkanen, M. O.; Miettinen,
R.; Rissanen, J.; Kekalainen, P.; Kuusisto, J.; Yla-Herttuala, S.;
Laakso, M.: Gene encoding the catalytic subunit p110-beta of human
phosphatidylinositol 3-kinase: cloning, genomic structure, and screening
for variants in patients with type 2 diabetes. Diabetes 49: 1740-1743,
2000.
7. Le Stunff, C.; Dechartres, A.; Del Giudice, E. M.; Froguel, P.;
Bougneres, P.: A single-nucleotide polymorphism in the p110-beta
gene promoter is associated with partial protection from insulin resistance
in severely obese adolescents. J. Clin. Endocr. Metab. 93: 212-215,
2008.
8. Liu, Z.; Hou, P.; Ji, M., H.; Studeman, K.; Jensen, K; Vasko, V.;
El-Naggar, A. K.; Xing, M.: Highly prevalent genetic alterations
in receptor tyrosine kinases and phosphatidylinositol 3-kinase/Akt
and mitogen-activated protein kinase pathways in anaplastic and follicular
thyroid cancers. J. Clin. Endocr. Metab. 93: 3106-3116, 2008.
*FIELD* CN
Patricia A. Hartz - updated: 11/15/2011
John A. Phillips, III - updated: 5/15/2009
John A. Phillips, III - updated: 5/7/2009
Ada Hamosh - updated: 9/24/2008
Anne M. Stumpf - updated: 10/25/2005
Patricia A. Hartz - updated: 5/16/2005
John A. Phillips, III - updated: 7/29/2004
*FIELD* CD
Rebekah S. Rasooly: 8/4/1998
*FIELD* ED
mgross: 11/06/2013
mgross: 2/7/2012
terry: 11/15/2011
alopez: 5/15/2009
alopez: 5/7/2009
alopez: 9/24/2008
terry: 9/24/2008
alopez: 10/25/2005
terry: 10/12/2005
mgross: 5/17/2005
terry: 5/16/2005
alopez: 7/29/2004
carol: 7/6/1999
alopez: 8/4/1998
*RECORD*
*FIELD* NO
602925
*FIELD* TI
*602925 PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, BETA; PIK3CB
;;PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, 110-KD, BETA;;
read morep110-BETA;;
PI3KCB;;
PI3K-BETA;;
PIK3-BETA
*FIELD* TX
DESCRIPTION
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position
of the inositol ring of inositol lipids. They have been implicated as
participants in signaling pathways regulating cell growth by virtue of
their activation in response to various mitogenic stimuli. PI3Ks are
composed of a 110-kD catalytic subunit, such as PIK3CB, and an 85-kD
adaptor subunit (Hu et al., 1993).
CLONING
To identify human genes encoding the PI3K catalytic subunit, Hu et al.
(1993) carried out RT-PCR with RNA from a T-lymphocyte cell line and
degenerate primers based on regions conserved between a bovine and a
yeast PI3K. The authors recovered a partial cDNA encoding a human PI3K
and used it to isolate additional cDNAs from an embryonic kidney cell
line (293) library. The predicted 1,070-amino acid protein, called
p110-beta by them, is 42% identical to that of bovine p110. Northern
blot analysis revealed that the major 4.8-kb p110-beta transcript was
expressed in several human and rodent cell lines, as well as in all
mouse tissues tested. Minor larger transcripts were detected in some
tissues and cell lines.
GENE FUNCTION
Using 293 cells expressing epitope tagged p110-beta, Hu et al. (1993)
demonstrated that the protein has PI3K activity. Antibodies against
p110-beta immunoprecipitated an endogenous PI3K activity from 293 cell
lysates. Both the epitope-tagged protein and endogenous p110-beta
associated with the 85-kD subunit in vivo.
Using flow-based adhesion assays with mouse and human platelets, Jackson
et al. (2005) determined that p110-beta has a role in regulating the
formation and stability of alpha-2B (ITGA2B; 607759)-beta-3 (ITGB3;
173470) integrin adhesion bonds, which are necessary for shear
force-induced platelet activation. p100-beta sustained alpha-2B-beta-3
integrin activation and stabilized platelet aggregation by regulating
both integrin-dependent calcium flux and Gi (see GNAI1; 139310)
activation of RAP1B (179530).
GENE STRUCTURE
Kossila et al. (2000) determined that the PIK3CB gene contains 22 exons
that are 51 to 252 basepairs in length.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PIK3CB
gene to chromosome 3 (TMAP WI-14619).
MOLECULAR GENETICS
Downregulation of the IGF1 (147440) pathway or IGF1 plasma levels is
associated with an increased life span. Bonafe et al. (2003) tested the
hypothesis that polymorphic variants of genes in the IGF1 response
pathway, namely IGF1R (147370) (G/A, codon 1013), PI3KCB (T/C, -359 bp;
A/G, -303 bp), IRS1 (147545) (G/A, codon 972), and FOXO1A (136533) (T/C,
+97347 bp), play a role in systemic IGF1 regulation and human longevity.
The major finding of this investigation was that subjects carrying at
least an A allele at IGF1R had low levels of free plasma IGF1 and were
more represented among long-lived people. Moreover, genotype
combinations at IGF1R and PIK3CB genes affect free IGF1 plasma levels
and longevity. Genotype combinations of an A allele at the IGF1R locus
and a T allele at the PI3CKB locus (A+/T+ subjects) affected IGF1 plasma
levels (with A-/T- individuals having the highest free IGF1 plasma
levels), as well as longevity, and the proportion of A+/T+ subjects
significantly increased among long-lived individuals.
Liu et al. (2008) explored a wide-range genetic basis for the
involvement of genetic alterations in receptor tyrosine kinases (RTKs)
and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in
anaplastic thyroid cancer (ATC) and follicular thyroid cancer (FTC;
188470). They found frequent copy gains of RTK genes including EGFR
(131550), and VEGFR1 (165070), and PIK3CA (171834) and PIK3CB in the
P13K/Akt pathway. Copy number gain of PIK3CB was found in 16 of 42 ATCs
(38%) and 25 of 55 FTCs (46%). RTK gene copy gains were preferentially
associated with phosphorylation of Akt, suggesting their dominant role
in activating the P13K/Akt pathway. Liu et al. (2008) concluded that
genetic alterations in the RTKs and P13K/Akt and MAPK pathways are
extremely prevalent in ATC and FTC, providing a strong genetic basis for
an extensive role of these signaling pathways and the development of
therapies targeting these pathways for ATC and FTC, particularly the
former.
Le Stunff et al. (2008) studied the p110-beta gene as a candidate gene
for association with insulin resistance (IR) and fasting glycemia in
severely obese children. They found that a SNP (dbSNP rs361072) located
in the promoter of the p110-beta gene was associated with fasting
glucose (P = 0.0002), insulin (P = 2.6 x 10(-8)), and homeostasis model
assessment insulin resistance index (P = 1 x 10(-9)) in severely obese
children. The effect of dbSNP rs361072 was marginal or not significant
in nonobese children. Le Stunff et al. (2008) concluded that the C
allele of dbSNP rs361072 attenuates IR in superobese children.
ANIMAL MODEL
To investigate distinct functions of p110-beta, Jia et al. (2008)
constructed conditional knockout mice. Ablation of p110-beta in the
livers of the resulting mice led to impaired insulin sensitivity and
glucose homeostasis, while having little effect on phosphorylation of
Akt (164730), suggesting the involvement of a kinase-independent role of
p110-beta in insulin metabolic action. Using established mouse embryonic
fibroblasts, Jia et al. (2008) found that removal of p110-beta also had
little effect on Akt phosphorylation in response to stimulation by
insulin and epidermal growth factor, but resulted in retarded cell
proliferation. Reconstitution of p110-beta-null cells with a wildtype or
kinase-dead allele of p110-beta demonstrated that p110-beta possesses
kinase-independent functions in regulating cell proliferation and
trafficking. However, the kinase activity of p110-beta was required for
G protein-coupled receptor signaling triggered by lysophosphatidic acid
and had a function in oncogenic transformation. Most strikingly, in an
animal model of prostate tumor formation induced by Pten (601728) loss,
ablation of p110-beta, but not that of p110-alpha (171834), impeded
tumorigenesis with a concomitant diminution of Akt phosphorylation. Jia
et al. (2008) concluded that, taken together, their findings
demonstrated both kinase-dependent and kinase-independent functions for
p110-beta.
Ciraolo et al. (2010) developed a line of mice expressing catalytically
inactive Pic3cb. Homozygous mutant mice were born and reached adulthood,
but while homozygous mutant females were fully fertile, homozygous
mutant males were subfertile. Mutant testis was reduced in size compared
with wildtype and immunohistochemical analysis revealed few spermatozoa
and hypocellular seminiferous tubules. Plasma testosterone was normal,
and FSH (see 136530) was elevated, suggesting primary gonadic failure in
mutant mice. Spermatogenic stem cell populations were observed, but they
were progressively lost, suggesting that inactivation of Pic3cb results
in a defect in spermatogenesis at later developmental stages. Kit
(164920)-positive cells were lost in adult mutant testis, and
pharmacologic inhibition of wildtype Pic3cb confirmed that Pic3cb is
downstream of Kit activation.
*FIELD* RF
1. Bonafe, M.; Barbieri, M.; Marchegiani, F.; Olivieri, F.; Ragno,
E.; Giampieri, C.; Mugianesi, E.; Centurelli, M.; Franceschi, C. and
Paolisso, G.: Polymorphic variants of insulin-like growth factor
I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I
plasma levels and human longevity: cues for an evolutionarily conserved
mechanism of life span control. J. Clin. Endocr. Metab. 88: 3299-3304,
2003.
2. Ciraolo, E.; Morello, F.; Hobbs, R. M.; Wolf, F.; Marone, R.; Iezzi,
M.; Lu, X.; Mengozzi, G.; Altruda, F.; Sorba, G.; Guan, K.; Pandolfi,
P. P.; Wymann, M. P.; Hirsch, E.: Essential role of the p110-beta
subunit of phosphoinositide 3-OH kinase in male fertility. Molec.
Biol. Cell 21: 704-711, 2010.
3. Hu, P.; Mondino, A.; Skolnik, E. Y.; Schlessinger, J.: Cloning
of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase
and identification of its binding site on p85. Molec. Cell. Biol. 13:
7677-7688, 1993.
4. Jackson, S. P.; Schoenwaelder, S. M.; Goncalves, I.; Nesbitt, W.
S.; Yap, C. L.; Wright, C. E.; Kenche, V.; Anderson, K. E.; Dopheide,
S. M.; Yuan, Y.; Sturgeon, S. A.; Prabaharan, H.; and 14 others
: PI 3-kinase p110-beta: a new target for antithrombotic therapy. Nature
Med. 11: 507-514, 2005.
5. Jia, S.; Liu, Z.; Zhang, S.; Liu, P.; Zhang, L.; Lee, S. H.; Zhang,
J.; Signoretti, S.; Loda, M.; Roberts, T. M.; Zhao, J. J.: Essential
roles of PI(3)K-p110-beta in cell growth, metabolism and tumorigenesis. Nature 454:
776-779, 2008.
6. Kossila, M.; Sinkovic, M.; Karkkainen, P.; Laukkanen, M. O.; Miettinen,
R.; Rissanen, J.; Kekalainen, P.; Kuusisto, J.; Yla-Herttuala, S.;
Laakso, M.: Gene encoding the catalytic subunit p110-beta of human
phosphatidylinositol 3-kinase: cloning, genomic structure, and screening
for variants in patients with type 2 diabetes. Diabetes 49: 1740-1743,
2000.
7. Le Stunff, C.; Dechartres, A.; Del Giudice, E. M.; Froguel, P.;
Bougneres, P.: A single-nucleotide polymorphism in the p110-beta
gene promoter is associated with partial protection from insulin resistance
in severely obese adolescents. J. Clin. Endocr. Metab. 93: 212-215,
2008.
8. Liu, Z.; Hou, P.; Ji, M., H.; Studeman, K.; Jensen, K; Vasko, V.;
El-Naggar, A. K.; Xing, M.: Highly prevalent genetic alterations
in receptor tyrosine kinases and phosphatidylinositol 3-kinase/Akt
and mitogen-activated protein kinase pathways in anaplastic and follicular
thyroid cancers. J. Clin. Endocr. Metab. 93: 3106-3116, 2008.
*FIELD* CN
Patricia A. Hartz - updated: 11/15/2011
John A. Phillips, III - updated: 5/15/2009
John A. Phillips, III - updated: 5/7/2009
Ada Hamosh - updated: 9/24/2008
Anne M. Stumpf - updated: 10/25/2005
Patricia A. Hartz - updated: 5/16/2005
John A. Phillips, III - updated: 7/29/2004
*FIELD* CD
Rebekah S. Rasooly: 8/4/1998
*FIELD* ED
mgross: 11/06/2013
mgross: 2/7/2012
terry: 11/15/2011
alopez: 5/15/2009
alopez: 5/7/2009
alopez: 9/24/2008
terry: 9/24/2008
alopez: 10/25/2005
terry: 10/12/2005
mgross: 5/17/2005
terry: 5/16/2005
alopez: 7/29/2004
carol: 7/6/1999
alopez: 8/4/1998