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O00443

- P3C2A_HUMAN

UniProt

O00443 - P3C2A_HUMAN

Protein

Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha

Gene

PIK3C2A

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 132 (01 Oct 2014)
      Sequence version 2 (10 Jul 2007)
      Previous versions | rss
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    Functioni

    Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers. Has a role in several intracellular trafficking events. Functions in insulin signaling and secretion. Required for translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane and glucose uptake in response to insulin-mediated RHOQ activation. Regulates insulin secretion through two different mechanisms: involved in glucose-induced insulin secretion downstream of insulin receptor in a pathway that involves AKT1 activation and TBC1D4/AS160 phosphorylation, and participates in the late step of insulin granule exocytosis probably in insulin granule fusion. Synthesizes PtdIns3P in response to insulin signaling. Functions in clathrin-coated endocytic vesicle formation and distribution. Regulates dynamin-independent endocytosis, probably by recruiting EEA1 to internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on large dense core vesicles. Participates in calcium induced contraction of vascular smooth muscle by regulating myosin light chain (MLC) phosphorylation through a mechanism involving Rho kinase-dependent phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role in the EGF signaling cascade. May be involved in mitosis and UV-induced damage response. Required for maintenance of normal renal structure and function by supporting normal podocyte function.7 Publications

    Catalytic activityi

    ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate.

    Cofactori

    Calcium or magnesium. Manganese cannot be used.2 Publications

    Enzyme regulationi

    Activated by insulin By similarity. Only slightly inhibited by wortmannin and LY294002. Activated by clathrin.By similarity3 Publications

    Kineticsi

    In the absence of the carrier phosphatidylserine, enzymatic kinetics toward PtdIns4P are non-linear.

    1. KM=122 µM for PtdIns (in the absence of phosphatidylserine)1 Publication
    2. KM=64 µM for PtdIns (in the presence of phosphatidylserine)1 Publication
    3. KM=25 µM for PtdIns4P (in the presence of phosphatidylserine)1 Publication
    4. KM=15 µM for ATP (with PtdIns as substrate) (in the absence of phosphatidylserine)1 Publication
    5. KM=32 µM for ATP (with PtdIns as substrate) (in the presence of phosphatidylserine)1 Publication
    6. KM=54 µM for ATP (with PtdIns4P as substrate) (in the presence of phosphatidylserine)1 Publication

    Vmax=990 pmol/min/mg enzyme with PtdIns as substrate (in the absence of phosphatidylserine)1 Publication

    Vmax=200 pmol/min/mg enzyme with PtdIns as substrate (in the presence of phosphatidylserine)1 Publication

    Vmax=240 pmol/min/mg enzyme with PtdIns4P as substrate (in the presence of phosphatidylserine)1 Publication

    Vmax=6800 pmol/min/mg enzyme toward ATP with PtdIns as substrate (in the absence of phosphatidylserine)1 Publication

    Vmax=805 pmol/min/mg enzyme toward ATP with PtdIns as substrate (in the presence of phosphatidylserine)1 Publication

    Vmax=880 pmol/min/mg enzyme toward ATP with PtdIns4P as substrate (in the presence of phosphatidylserine)1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei244 – 2441Not phosphorylated
    Sitei249 – 2491Not phosphorylated
    Sitei251 – 2511Not phosphorylated
    Sitei254 – 2541Not phosphorylated
    Sitei262 – 2621Not phosphorylated
    Sitei266 – 2661Not phosphorylated

    GO - Molecular functioni

    1. 1-phosphatidylinositol-3-kinase activity Source: RefGenome
    2. 1-phosphatidylinositol-4-phosphate 3-kinase activity Source: Reactome
    3. ATP binding Source: UniProtKB-KW
    4. phosphatidylinositol 3-kinase activity Source: UniProtKB
    5. phosphatidylinositol binding Source: InterPro

    GO - Biological processi

    1. clathrin coat assembly Source: UniProtKB
    2. endocytosis Source: UniProtKB
    3. epidermal growth factor receptor signaling pathway Source: UniProtKB
    4. exocytosis Source: UniProtKB
    5. insulin receptor signaling pathway Source: UniProtKB
    6. phosphatidylinositol biosynthetic process Source: Reactome
    7. phosphatidylinositol-mediated signaling Source: InterPro
    8. phospholipid metabolic process Source: Reactome
    9. platelet-derived growth factor receptor signaling pathway Source: UniProtKB
    10. small molecule metabolic process Source: Reactome
    11. vascular smooth muscle contraction Source: UniProtKB

    Keywords - Molecular functioni

    Kinase, Transferase

    Keywords - Biological processi

    Endocytosis, Exocytosis

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:HS00315-MONOMER.
    BRENDAi2.7.1.154. 2681.
    ReactomeiREACT_120756. Synthesis of PIPs at the early endosome membrane.
    REACT_120836. Synthesis of PIPs at the Golgi membrane.
    REACT_120918. Synthesis of PIPs at the late endosome membrane.
    REACT_121025. Synthesis of PIPs at the plasma membrane.
    REACT_19400. Golgi Associated Vesicle Biogenesis.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (EC:2.7.1.154)
    Short name:
    PI3K-C2-alpha
    Short name:
    PtdIns-3-kinase C2 subunit alpha
    Alternative name(s):
    Phosphoinositide 3-kinase-C2-alpha
    Gene namesi
    Name:PIK3C2A
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 11

    Organism-specific databases

    HGNCiHGNC:8971. PIK3C2A.

    Subcellular locationi

    Cell membrane. Golgi apparatus. Cytoplasmic vesicleclathrin-coated vesicle. Nucleus. Cytoplasm
    Note: According to PubMed:10766823 and PubMed:11239472, it is found in the cell membrane, the Golgi apparatus and in clathrin-coated vesicles. According to PubMed:17038310 it inserts preferentially into membranes containing PtdIns(4,5)P2. According to PubMed:11606566, it is nuclear and cytoplasmic. Associated with RNA-containing structures. According to PubMed:14563213, it is mainly cytoplasmic.

    GO - Cellular componenti

    1. clathrin-coated vesicle Source: UniProtKB-SubCell
    2. cytoplasm Source: UniProtKB
    3. cytosol Source: Reactome
    4. extracellular vesicular exosome Source: UniProt
    5. Golgi apparatus Source: UniProtKB-SubCell
    6. membrane Source: UniProtKB
    7. nucleus Source: UniProtKB-SubCell
    8. phosphatidylinositol 3-kinase complex Source: RefGenome
    9. plasma membrane Source: UniProtKB
    10. vesicle Source: UniProtKB

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Cytoplasmic vesicle, Golgi apparatus, Membrane, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi103 – 1075LLLDD → AAAAA: Reduces clathrin binding. 1 Publication
    Mutagenesisi254 – 2541S → A: No effect on phosphorylation in vitro. 2 Publications
    Mutagenesisi259 – 2591S → A, D or E: Abolishes phosphorylation, no change in activity. 2 Publications
    Mutagenesisi259 – 2591S → A: Protects from proteolysis. 2 Publications
    Mutagenesisi262 – 2621S → A: No effect on phosphorylation in vitro. 2 Publications
    Mutagenesisi266 – 2661S → A: No effect on phosphorylation in vitro. 2 Publications
    Mutagenesisi1250 – 12501D → A: Abolishes lipid kinase activity. Affects clathrin distribution when combined with a truncation encompassing the region of clathrin interaction. 2 Publications
    Mutagenesisi1488 – 14881R → A: Reduces affinity for PtdIns(4,5)P2-containing membranes 7-fold. 2 Publications
    Mutagenesisi1490 – 14901V → A: Reduces affinity for PtdIns(4,5)P2-containing membranes 7-fold. 2 Publications
    Mutagenesisi1491 – 14911L → A: Reduces affinity for PtdIns(4,5)P2-containing membranes 5-fold. 2 Publications
    Mutagenesisi1493 – 14931R → A: Reduces affinity for PtdIns(4,5)P2-containing membranes 23-fold. 2 Publications
    Mutagenesisi1503 – 15031R → A: Abolishes interaction with PtdIns(4,5)P2-containing membranes. 2 Publications

    Organism-specific databases

    PharmGKBiPA33304.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed1 Publication
    Chaini2 – 16861685Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alphaPRO_0000088795Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylalanine1 Publication
    Modified residuei60 – 601Phosphoserine2 Publications
    Modified residuei108 – 1081Phosphoserine4 Publications
    Modified residuei259 – 2591Phosphoserine8 Publications
    Modified residuei327 – 3271Phosphoserine2 Publications
    Modified residuei338 – 3381Phosphoserine2 Publications

    Post-translational modificationi

    Phosphorylated upon insulin stimulation; which may lead to enzyme activation By similarity. Phosphorylated on Ser-259 during mitosis and upon UV irradiation; which does not change enzymatic activity but leads to proteasomal degradation. Ser-259 phosphorylation may be mediated by CDK1 or JNK, depending on the physiological state of the cell.By similarity8 Publications

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiO00443.
    PaxDbiO00443.
    PRIDEiO00443.

    PTM databases

    PhosphoSiteiO00443.

    Expressioni

    Tissue specificityi

    Expressed in columnar and transitional epithelia, mononuclear cells, smooth muscle cells, and endothelial cells lining capillaries and small venules (at protein level). Ubiquitously expressed, with highest levels in heart, placenta and ovary, and lowest levels in the kidney. Detected at low levels in islets of Langerhans from type 2 diabetes mellitus individuals.3 Publications

    Gene expression databases

    ArrayExpressiO00443.
    BgeeiO00443.
    CleanExiHS_PIK3C2A.
    GenevestigatoriO00443.

    Organism-specific databases

    HPAiHPA037641.
    HPA037642.

    Interactioni

    Subunit structurei

    Part of a complex with ERBB2 and EGFR. Interacts with clathrin trimers.3 Publications

    Protein-protein interaction databases

    BioGridi111304. 20 interactions.
    IntActiO00443. 16 interactions.
    MINTiMINT-2794824.
    STRINGi9606.ENSP00000265970.

    Structurei

    Secondary structure

    1
    1686
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi1418 – 14214
    Beta strandi1422 – 143312
    Beta strandi1437 – 14404
    Beta strandi1443 – 14508
    Beta strandi1457 – 14626
    Helixi1463 – 147614
    Helixi1479 – 14813
    Beta strandi1491 – 14955
    Helixi1498 – 151518
    Helixi1519 – 15224
    Helixi1525 – 15306
    Turni1535 – 15373

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2AR5X-ray1.80A1421-1532[»]
    2IWLX-ray2.60X1405-1544[»]
    2REAX-ray2.50A1421-1532[»]
    2REDX-ray2.10A1421-1532[»]
    ProteinModelPortaliO00443.
    SMRiO00443. Positions 666-1391, 1421-1532, 1561-1682.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO00443.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini421 – 50989PI3K-RBDPROSITE-ProRule annotationAdd
    BLAST
    Domaini682 – 841160C2 PI3K-typePROSITE-ProRule annotationAdd
    BLAST
    Domaini861 – 1037177PIK helicalPROSITE-ProRule annotationAdd
    BLAST
    Domaini1133 – 1397265PI3K/PI4KPROSITE-ProRule annotationAdd
    BLAST
    Domaini1422 – 1538117PXPROSITE-ProRule annotationAdd
    BLAST
    Domaini1559 – 1662104C2PROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni2 – 142141Interaction with clathrin; sufficient to induce clathrin assembyAdd
    BLAST
    Regioni1488 – 14936Interaction with PtdIns(4,5)P2-containing membranes

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi1608 – 161912Nuclear localization signal1 PublicationAdd
    BLAST

    Sequence similaritiesi

    Belongs to the PI3/PI4-kinase family.PROSITE-ProRule annotation
    Contains 1 C2 domain.PROSITE-ProRule annotation
    Contains 1 C2 PI3K-type domain.PROSITE-ProRule annotation
    Contains 1 PI3K-RBD domain.PROSITE-ProRule annotation
    Contains 1 PI3K/PI4K domain.PROSITE-ProRule annotation
    Contains 1 PIK helical domain.PROSITE-ProRule annotation
    Contains 1 PX (phox homology) domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG5032.
    HOGENOMiHOG000006920.
    HOVERGENiHBG082099.
    InParanoidiO00443.
    KOiK00923.
    OMAiKCRLPLN.
    OrthoDBiEOG71CFK4.
    PhylomeDBiO00443.
    TreeFamiTF102031.

    Family and domain databases

    Gene3Di1.10.1070.11. 1 hit.
    1.25.40.70. 1 hit.
    2.60.40.150. 2 hits.
    3.30.1520.10. 1 hit.
    InterProiIPR016024. ARM-type_fold.
    IPR000008. C2_dom.
    IPR011009. Kinase-like_dom.
    IPR001683. Phox.
    IPR000403. PI3/4_kinase_cat_dom.
    IPR018936. PI3/4_kinase_CS.
    IPR002420. PI3K_C2_dom.
    IPR000341. PI3K_Ras-bd_dom.
    IPR015433. PI_Kinase.
    IPR001263. PInositide-3_kin_accessory_dom.
    IPR029071. Ubiquitin-rel_dom.
    [Graphical view]
    PANTHERiPTHR10048. PTHR10048. 1 hit.
    PfamiPF00168. C2. 1 hit.
    PF00454. PI3_PI4_kinase. 1 hit.
    PF00792. PI3K_C2. 1 hit.
    PF00794. PI3K_rbd. 1 hit.
    PF00613. PI3Ka. 1 hit.
    PF00787. PX. 1 hit.
    [Graphical view]
    SMARTiSM00239. C2. 2 hits.
    SM00142. PI3K_C2. 1 hit.
    SM00144. PI3K_rbd. 1 hit.
    SM00145. PI3Ka. 1 hit.
    SM00146. PI3Kc. 1 hit.
    SM00312. PX. 1 hit.
    [Graphical view]
    SUPFAMiSSF48371. SSF48371. 1 hit.
    SSF49562. SSF49562. 2 hits.
    SSF54236. SSF54236. 1 hit.
    SSF56112. SSF56112. 1 hit.
    SSF64268. SSF64268. 1 hit.
    PROSITEiPS50004. C2. 1 hit.
    PS00915. PI3_4_KINASE_1. 1 hit.
    PS00916. PI3_4_KINASE_2. 1 hit.
    PS50290. PI3_4_KINASE_3. 1 hit.
    PS51547. PI3K_C2. 1 hit.
    PS51546. PI3K_RBD. 1 hit.
    PS51545. PIK_HELICAL. 1 hit.
    PS50195. PX. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: O00443-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MAQISSNSGF KECPSSHPEP TRAKDVDKEE ALQMEAEALA KLQKDRQVTD     50
    NQRGFELSSS TRKKAQVYNK QDYDLMVFPE SDSQKRALDI DVEKLTQAEL 100
    EKLLLDDSFE TKKTPVLPVT PILSPSFSAQ LYFRPTIQRG QWPPGLPGPS 150
    TYALPSIYPS TYSKQAAFQN GFNPRMPTFP STEPIYLSLP GQSPYFSYPL 200
    TPATPFHPQG SLPIYRPVVS TDMAKLFDKI ASTSEFLKNG KARTDLEITD 250
    SKVSNLQVSP KSEDISKFDW LDLDPLSKPK VDNVEVLDHE EEKNVSSLLA 300
    KDPWDAVLLE ERSTANCHLE RKVNGKSLSV ATVTRSQSLN IRTTQLAKAQ 350
    GHISQKDPNG TSSLPTGSSL LQEVEVQNEE MAAFCRSITK LKTKFPYTNH 400
    RTNPGYLLSP VTAQRNICGE NASVKVSIDI EGFQLPVTFT CDVSSTVEII 450
    IMQALCWVHD DLNQVDVGSY VLKVCGQEEV LQNNHCLGSH EHIQNCRKWD 500
    TEIRLQLLTF SAMCQNLART AEDDETPVDL NKHLYQIEKP CKEAMTRHPV 550
    EELLDSYHNQ VELALQIENQ HRAVDQVIKA VRKICSALDG VETLAITESV 600
    KKLKRAVNLP RSKTADVTSL FGGEDTSRSS TRGSLNPENP VQVSINQLTA 650
    AIYDLLRLHA NSGRSPTDCA QSSKSVKEAW TTTEQLQFTI FAAHGISSNW 700
    VSNYEKYYLI CSLSHNGKDL FKPIQSKKVG TYKNFFYLIK WDELIIFPIQ 750
    ISQLPLESVL HLTLFGILNQ SSGSSPDSNK QRKGPEALGK VSLPLFDFKR 800
    FLTCGTKLLY LWTSSHTNSV PGTVTKKGYV MERIVLQVDF PSPAFDIIYT 850
    TPQVDRSIIQ QHNLETLEND IKGKLLDILH KDSSLGLSKE DKAFLWEKRY 900
    YCFKHPNCLP KILASAPNWK WVNLAKTYSL LHQWPALYPL IALELLDSKF 950
    ADQEVRSLAV TWIEAISDDE LTDLLPQFVQ ALKYEIYLNS SLVQFLLSRA 1000
    LGNIQIAHNL YWLLKDALHD VQFSTRYEHV LGALLSVGGK RLREELLKQT 1050
    KLVQLLGGVA EKVRQASGSA RQVVLQRSME RVQSFFQKNK CRLPLKPSLV 1100
    AKELNIKSCS FFSSNAVPLK VTMVNADPMG EEINVMFKVG EDLRQDMLAL 1150
    QMIKIMDKIW LKEGLDLRMV IFKCLSTGRD RGMVELVPAS DTLRKIQVEY 1200
    GVTGSFKDKP LAEWLRKYNP SEEEYEKASE NFIYSCAGCC VATYVLGICD 1250
    RHNDNIMLRS TGHMFHIDFG KFLGHAQMFG SFKRDRAPFV LTSDMAYVIN 1300
    GGEKPTIRFQ LFVDLCCQAY NLIRKQTNLF LNLLSLMIPS GLPELTSIQD 1350
    LKYVRDALQP QTTDAEATIF FTRLIESSLG SIATKFNFFI HNLAQLRFSG 1400
    LPSNDEPILS FSPKTYSFRQ DGRIKEVSVF TYHKKYNPDK HYIYVVRILR 1450
    EGQIEPSFVF RTFDEFQELH NKLSIIFPLW KLPGFPNRMV LGRTHIKDVA 1500
    AKRKIELNSY LQSLMNASTD VAECDLVCTF FHPLLRDEKA EGIARSADAG 1550
    SFSPTPGQIG GAVKLSISYR NGTLFIMVMH IKDLVTEDGA DPNPYVKTYL 1600
    LPDNHKTSKR KTKISRKTRN PTFNEMLVYS GYSKETLRQR ELQLSVLSAE 1650
    SLRENFFLGG VTLPLKDFNL SKETVKWYQL TAATYL 1686
    Length:1,686
    Mass (Da):190,680
    Last modified:July 10, 2007 - v2
    Checksum:i904AA5470F80DAC6
    GO
    Isoform 2 (identifier: O00443-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         484-1686: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:483
    Mass (Da):53,742
    Checksum:iB63EDBEA18725E91
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti5 – 51S → F in CAA73797. (PubMed:9337861)Curated
    Sequence conflicti15 – 151S → F in CAA73797. (PubMed:9337861)Curated
    Sequence conflicti483 – 4831N → K in BAG65126. (PubMed:14702039)Curated
    Sequence conflicti796 – 7961F → C in CAA73797. (PubMed:9337861)Curated
    Sequence conflicti799 – 7991K → R in CAA73797. (PubMed:9337861)Curated
    Sequence conflicti922 – 9221V → G in CAA73797. (PubMed:9337861)Curated
    Sequence conflicti1129 – 11291M → L in CAA73797. (PubMed:9337861)Curated
    Sequence conflicti1450 – 14501R → W in CAA73797. (PubMed:9337861)Curated
    Sequence conflicti1464 – 14641D → V in CAA73797. (PubMed:9337861)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti1415 – 14151T → A.
    Corresponds to variant rs11604561 [ dbSNP | Ensembl ].
    VAR_023333

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei484 – 16861203Missing in isoform 2. 1 PublicationVSP_056158Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    Y13367 mRNA. Translation: CAA73797.1.
    AK304262 mRNA. Translation: BAG65126.1.
    EU332862 Genomic DNA. Translation: ABY87551.1.
    AC107956 Genomic DNA. No translation available.
    AC116533 Genomic DNA. No translation available.
    AC126389 Genomic DNA. No translation available.
    CH471064 Genomic DNA. Translation: EAW68447.1.
    BC113658 mRNA. Translation: AAI13659.1.
    CCDSiCCDS7824.1.
    PIRiPC4345.
    RefSeqiNP_002636.2. NM_002645.2.
    XP_005253034.1. XM_005252977.1.
    XP_005253035.1. XM_005252978.2.
    XP_005253036.1. XM_005252979.2.
    UniGeneiHs.175343.

    Genome annotation databases

    EnsembliENST00000265970; ENSP00000265970; ENSG00000011405.
    ENST00000533645; ENSP00000436244; ENSG00000011405.
    GeneIDi5286.
    KEGGihsa:5286.
    UCSCiuc001mmq.4. human.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    Y13367 mRNA. Translation: CAA73797.1 .
    AK304262 mRNA. Translation: BAG65126.1 .
    EU332862 Genomic DNA. Translation: ABY87551.1 .
    AC107956 Genomic DNA. No translation available.
    AC116533 Genomic DNA. No translation available.
    AC126389 Genomic DNA. No translation available.
    CH471064 Genomic DNA. Translation: EAW68447.1 .
    BC113658 mRNA. Translation: AAI13659.1 .
    CCDSi CCDS7824.1.
    PIRi PC4345.
    RefSeqi NP_002636.2. NM_002645.2.
    XP_005253034.1. XM_005252977.1.
    XP_005253035.1. XM_005252978.2.
    XP_005253036.1. XM_005252979.2.
    UniGenei Hs.175343.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2AR5 X-ray 1.80 A 1421-1532 [» ]
    2IWL X-ray 2.60 X 1405-1544 [» ]
    2REA X-ray 2.50 A 1421-1532 [» ]
    2RED X-ray 2.10 A 1421-1532 [» ]
    ProteinModelPortali O00443.
    SMRi O00443. Positions 666-1391, 1421-1532, 1561-1682.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 111304. 20 interactions.
    IntActi O00443. 16 interactions.
    MINTi MINT-2794824.
    STRINGi 9606.ENSP00000265970.

    Chemistry

    BindingDBi O00443.
    ChEMBLi CHEMBL1075102.
    DrugBanki DB00144. Phosphatidylserine.

    PTM databases

    PhosphoSitei O00443.

    Proteomic databases

    MaxQBi O00443.
    PaxDbi O00443.
    PRIDEi O00443.

    Protocols and materials databases

    DNASUi 5286.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000265970 ; ENSP00000265970 ; ENSG00000011405 .
    ENST00000533645 ; ENSP00000436244 ; ENSG00000011405 .
    GeneIDi 5286.
    KEGGi hsa:5286.
    UCSCi uc001mmq.4. human.

    Organism-specific databases

    CTDi 5286.
    GeneCardsi GC11M017099.
    HGNCi HGNC:8971. PIK3C2A.
    HPAi HPA037641.
    HPA037642.
    MIMi 603601. gene.
    neXtProti NX_O00443.
    PharmGKBi PA33304.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG5032.
    HOGENOMi HOG000006920.
    HOVERGENi HBG082099.
    InParanoidi O00443.
    KOi K00923.
    OMAi KCRLPLN.
    OrthoDBi EOG71CFK4.
    PhylomeDBi O00443.
    TreeFami TF102031.

    Enzyme and pathway databases

    BioCyci MetaCyc:HS00315-MONOMER.
    BRENDAi 2.7.1.154. 2681.
    Reactomei REACT_120756. Synthesis of PIPs at the early endosome membrane.
    REACT_120836. Synthesis of PIPs at the Golgi membrane.
    REACT_120918. Synthesis of PIPs at the late endosome membrane.
    REACT_121025. Synthesis of PIPs at the plasma membrane.
    REACT_19400. Golgi Associated Vesicle Biogenesis.

    Miscellaneous databases

    ChiTaRSi PIK3C2A. human.
    EvolutionaryTracei O00443.
    GeneWikii PIK3C2A.
    GenomeRNAii 5286.
    NextBioi 20426.
    PROi O00443.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O00443.
    Bgeei O00443.
    CleanExi HS_PIK3C2A.
    Genevestigatori O00443.

    Family and domain databases

    Gene3Di 1.10.1070.11. 1 hit.
    1.25.40.70. 1 hit.
    2.60.40.150. 2 hits.
    3.30.1520.10. 1 hit.
    InterProi IPR016024. ARM-type_fold.
    IPR000008. C2_dom.
    IPR011009. Kinase-like_dom.
    IPR001683. Phox.
    IPR000403. PI3/4_kinase_cat_dom.
    IPR018936. PI3/4_kinase_CS.
    IPR002420. PI3K_C2_dom.
    IPR000341. PI3K_Ras-bd_dom.
    IPR015433. PI_Kinase.
    IPR001263. PInositide-3_kin_accessory_dom.
    IPR029071. Ubiquitin-rel_dom.
    [Graphical view ]
    PANTHERi PTHR10048. PTHR10048. 1 hit.
    Pfami PF00168. C2. 1 hit.
    PF00454. PI3_PI4_kinase. 1 hit.
    PF00792. PI3K_C2. 1 hit.
    PF00794. PI3K_rbd. 1 hit.
    PF00613. PI3Ka. 1 hit.
    PF00787. PX. 1 hit.
    [Graphical view ]
    SMARTi SM00239. C2. 2 hits.
    SM00142. PI3K_C2. 1 hit.
    SM00144. PI3K_rbd. 1 hit.
    SM00145. PI3Ka. 1 hit.
    SM00146. PI3Kc. 1 hit.
    SM00312. PX. 1 hit.
    [Graphical view ]
    SUPFAMi SSF48371. SSF48371. 1 hit.
    SSF49562. SSF49562. 2 hits.
    SSF54236. SSF54236. 1 hit.
    SSF56112. SSF56112. 1 hit.
    SSF64268. SSF64268. 1 hit.
    PROSITEi PS50004. C2. 1 hit.
    PS00915. PI3_4_KINASE_1. 1 hit.
    PS00916. PI3_4_KINASE_2. 1 hit.
    PS50290. PI3_4_KINASE_3. 1 hit.
    PS51547. PI3K_C2. 1 hit.
    PS51546. PI3K_RBD. 1 hit.
    PS51545. PIK_HELICAL. 1 hit.
    PS50195. PX. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Cloning of a human phosphoinositide 3-kinase with a C2 domain which displays reduced sensitivity to the inhibitor wortmannin."
      Domin J., Pages F., Volinia S., Rittenhouse S.E., Zvelebil M.J., Stein R.C., Waterfield M.D.
      Biochem. J. 326:139-147(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, COFACTOR, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY.
    2. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
      Tissue: Trachea.
    3. NHLBI resequencing and genotyping service (RS&G)
      Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Tissue: Lung.
    7. "The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans-Golgi network and present in clathrin-coated vesicles."
      Domin J., Gaidarov I., Smith M.E.K., Keen J.H., Waterfield M.D.
      J. Biol. Chem. 275:11943-11950(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION.
    8. "Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors."
      Arcaro A., Zvelebil M.J., Wallasch C., Ullrich A., Waterfield M.D., Domin J.
      Mol. Cell. Biol. 20:3817-3830(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, COFACTOR, IDENTIFICATION IN A COMPLEX WITH ERBB2 AND EGFR.
    9. "Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization sequence and associates with nuclear speckles."
      Didichenko S.A., Thelen M.
      J. Biol. Chem. 276:48135-48142(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, PHOSPHORYLATION, IDENTIFICATION BY MASS SPECTROMETRY.
    10. "The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking."
      Gaidarov I., Smith M.E.K., Domin J., Keen J.H.
      Mol. Cell 7:443-449(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, INTERACTION WITH CLATHRIN, MUTAGENESIS OF 103-LEU--ASP-107.
    11. "Topographical expression of class IA and class II phosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation."
      El Sheikh S.S., Domin J., Tomtitchong P., Abel P., Stamp G., Lalani E.-N.
      BMC Clin. Pathol. 3:4-4(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    12. "Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation."
      Didichenko S.A., Fragoso C.M., Thelen M.
      J. Biol. Chem. 278:26055-26064(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT SER-259, MUTAGENESIS OF SER-254; SER-259; SER-262 AND SER-266, IDENTIFICATION BY MASS SPECTROMETRY.
    13. "Individual phosphoinositide 3-kinase C2alpha domain activities independently regulate clathrin function."
      Gaidarov I., Zhao Y., Keen J.H.
      J. Biol. Chem. 280:40766-40772(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN ASSEMBLY AND CELLULAR DISTRIBUTION OF CLATHRIN, INTERACTION WITH CLATHRIN, MUTAGENESIS OF ASP-1250, REGION.
    14. "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
      Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
      Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108 AND SER-259, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    15. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-60; SER-108; SER-259 AND SER-338, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    16. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
      Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
      Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
    17. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    18. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
      Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
      Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    19. "PI3KC2alpha, a class II PI3K, is required for dynamin-independent internalization pathways."
      Krag C., Malmberg E.K., Salcini A.E.
      J. Cell Sci. 123:4240-4250(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN DYNAMIN-INDEPENDENT ENDOCYTOSIS.
    20. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
      Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
      Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108 AND SER-259, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    21. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    22. Cited for: TISSUE SPECIFICITY.
    23. "Role of class II phosphoinositide 3-kinase in cell signalling."
      Falasca M., Maffucci T.
      Biochem. Soc. Trans. 35:211-214(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    24. "System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
      Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
      Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259 AND SER-327, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    25. "Structural and membrane binding analysis of the Phox homology domain of phosphoinositide 3-kinase-C2alpha."
      Stahelin R.V., Karathanassis D., Bruzik K.S., Waterfield M.D., Bravo J., Williams R.L., Cho W.
      J. Biol. Chem. 281:39396-39406(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 1405-1544, PHOSPHOINOSITIDE BINDING, SUBCELLULAR LOCATION, MUTAGENESIS OF ARG-1488; VAL-1490; LEU-1491; ARG-1493 AND ARG-1503.
    26. "Ligand-binding specificity of PI3kinase C2alpha PX domain."
      Parkinson G.N., Vines D., Driscoll P.C., Djordjevic S.
      Submitted (OCT-2006) to the PDB data bank
      Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1421-1532.

    Entry informationi

    Entry nameiP3C2A_HUMAN
    AccessioniPrimary (citable) accession number: O00443
    Secondary accession number(s): B0LPH2, B4E2G4, Q14CQ9
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: August 30, 2005
    Last sequence update: July 10, 2007
    Last modified: October 1, 2014
    This is version 132 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 11
      Human chromosome 11: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3