P3C2A_PONAB
ID P3C2A_PONAB Reviewed; 1685 AA.
AC Q5RAY1;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 108.
DE RecName: Full=Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha;
DE Short=PI3K-C2-alpha;
DE Short=PtdIns-3-kinase C2 subunit alpha;
DE EC=2.7.1.137 {ECO:0000250|UniProtKB:O00443};
DE EC=2.7.1.153 {ECO:0000250|UniProtKB:O00443};
DE EC=2.7.1.154 {ECO:0000250|UniProtKB:O00443};
DE AltName: Full=Phosphoinositide 3-kinase-C2-alpha;
GN Name=PIK3C2A;
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Generates phosphatidylinositol 3-phosphate (PtdIns3P) and
CC phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as
CC second messengers. Has a role in several intracellular trafficking
CC events. Functions in insulin signaling and secretion. Required for
CC translocation of the glucose transporter SLC2A4/GLUT4 to the plasma
CC membrane and glucose uptake in response to insulin-mediated RHOQ
CC activation. Regulates insulin secretion through two different
CC mechanisms: involved in glucose-induced insulin secretion downstream of
CC insulin receptor in a pathway that involves AKT1 activation and
CC TBC1D4/AS160 phosphorylation, and participates in the late step of
CC insulin granule exocytosis probably in insulin granule fusion.
CC Synthesizes PtdIns3P in response to insulin signaling. Functions in
CC clathrin-coated endocytic vesicle formation and distribution. Regulates
CC dynamin-independent endocytosis, probably by recruiting EEA1 to
CC internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on
CC large dense core vesicles. Participates in calcium induced contraction
CC of vascular smooth muscle by regulating myosin light chain (MLC)
CC phosphorylation through a mechanism involving Rho kinase-dependent
CC phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role
CC in the EGF signaling cascade. May be involved in mitosis and UV-induced
CC damage response. Required for maintenance of normal renal structure and
CC function by supporting normal podocyte function (By similarity).
CC Involved in the regulation of ciliogenesis and trafficking of ciliary
CC components (By similarity). {ECO:0000250|UniProtKB:O00443,
CC ECO:0000250|UniProtKB:Q61194}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-
CC phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4-bisphosphate) + ADP + H(+); Xref=Rhea:RHEA:18373,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57658,
CC ChEBI:CHEBI:58178, ChEBI:CHEBI:456216; EC=2.7.1.154;
CC Evidence={ECO:0000250|UniProtKB:O00443};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:18374;
CC Evidence={ECO:0000250|UniProtKB:O00443};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a
CC 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP +
CC H(+); Xref=Rhea:RHEA:12709, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:57880, ChEBI:CHEBI:58088, ChEBI:CHEBI:456216;
CC EC=2.7.1.137; Evidence={ECO:0000250|UniProtKB:O00443};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12710;
CC Evidence={ECO:0000250|UniProtKB:O00443};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-
CC bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4,5-trisphosphate) + ADP + H(+); Xref=Rhea:RHEA:21292,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57836,
CC ChEBI:CHEBI:58456, ChEBI:CHEBI:456216; EC=2.7.1.153;
CC Evidence={ECO:0000250|UniProtKB:O00443};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21293;
CC Evidence={ECO:0000250|UniProtKB:O00443};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:O00443};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:O00443};
CC Note=Ca(2+) or Mg(2+). Mn(2+) cannot be used.
CC {ECO:0000250|UniProtKB:O00443};
CC -!- ACTIVITY REGULATION: Only slightly inhibited by wortmannin and
CC LY294002. Activated by clathrin and insulin (By similarity).
CC {ECO:0000250|UniProtKB:O00443, ECO:0000250|UniProtKB:Q61194}.
CC -!- SUBUNIT: Part of a complex with ERBB2 and EGFR (By similarity).
CC Interacts with clathrin trimers (By similarity). Interacts with
CC SBF2/MTMR13 (By similarity). {ECO:0000250|UniProtKB:O00443,
CC ECO:0000250|UniProtKB:Q61194}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O00443}.
CC Cytoplasmic vesicle, clathrin-coated vesicle
CC {ECO:0000250|UniProtKB:O00443}. Nucleus {ECO:0000250|UniProtKB:O00443}.
CC Cytoplasm {ECO:0000250|UniProtKB:O00443}. Golgi apparatus, trans-Golgi
CC network {ECO:0000250|UniProtKB:O00443}. Note=Inserts preferentially
CC into membranes containing PtdIns(4,5)P2. Associated with RNA-containing
CC structures. {ECO:0000250|UniProtKB:O00443}.
CC -!- PTM: Phosphorylated on Ser-259 during mitosis and upon UV irradiation;
CC which does not change enzymatic activity but leads to proteasomal
CC degradation. Phosphorylated upon insulin stimulation; which may lead to
CC enzyme activation (By similarity). {ECO:0000250|UniProtKB:O00443,
CC ECO:0000250|UniProtKB:Q61194}.
CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. {ECO:0000255|PROSITE-
CC ProRule:PRU00879, ECO:0000255|PROSITE-ProRule:PRU00880}.
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DR EMBL; CR858880; CAH91079.1; -; mRNA.
DR RefSeq; NP_001125626.1; NM_001132154.1.
DR AlphaFoldDB; Q5RAY1; -.
DR SMR; Q5RAY1; -.
DR STRING; 9601.ENSPPYP00000003968; -.
DR GeneID; 100457125; -.
DR KEGG; pon:100457125; -.
DR CTD; 5286; -.
DR eggNOG; KOG0905; Eukaryota.
DR InParanoid; Q5RAY1; -.
DR OrthoDB; 204282at2759; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0030136; C:clathrin-coated vesicle; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0031982; C:vesicle; ISS:UniProtKB.
DR GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; ISS:UniProtKB.
DR GO; GO:0035005; F:1-phosphatidylinositol-4-phosphate 3-kinase activity; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0030276; F:clathrin binding; ISS:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; IEA:InterPro.
DR GO; GO:0052812; F:phosphatidylinositol-3,4-bisphosphate 5-kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; ISS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; ISS:UniProtKB.
DR GO; GO:0006887; P:exocytosis; IEA:UniProtKB-KW.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IEA:InterPro.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR CDD; cd05176; PI3Kc_C2_alpha; 1.
DR CDD; cd07289; PX_PI3K_C2_alpha; 1.
DR Gene3D; 1.10.1070.11; -; 1.
DR Gene3D; 1.25.40.70; -; 1.
DR Gene3D; 2.60.40.150; -; 2.
DR Gene3D; 3.30.1520.10; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR036940; PI3/4_kinase_cat_sf.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR037705; PI3K-C2-alpha_dom.
DR InterPro; IPR002420; PI3K-type_C2_dom.
DR InterPro; IPR001263; PI3K_accessory_dom.
DR InterPro; IPR042236; PI3K_accessory_sf.
DR InterPro; IPR000341; PI3K_Ras-bd_dom.
DR InterPro; IPR015433; PI_Kinase.
DR InterPro; IPR001683; PX_dom.
DR InterPro; IPR036871; PX_dom_sf.
DR InterPro; IPR042133; PX_PI3K_C2_alpha.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR PANTHER; PTHR10048; PTHR10048; 1.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF00454; PI3_PI4_kinase; 1.
DR Pfam; PF00792; PI3K_C2; 1.
DR Pfam; PF00794; PI3K_rbd; 1.
DR Pfam; PF00613; PI3Ka; 1.
DR Pfam; PF00787; PX; 1.
DR SMART; SM00239; C2; 2.
DR SMART; SM00142; PI3K_C2; 1.
DR SMART; SM00144; PI3K_rbd; 1.
DR SMART; SM00145; PI3Ka; 1.
DR SMART; SM00146; PI3Kc; 1.
DR SMART; SM00312; PX; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR SUPFAM; SSF49562; SSF49562; 2.
DR SUPFAM; SSF54236; SSF54236; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF64268; SSF64268; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS51547; C2_PI3K; 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; PS51546; PI3K_RBD; 1.
DR PROSITE; PS51545; PIK_HELICAL; 1.
DR PROSITE; PS50195; PX; 1.
PE 2: Evidence at transcript level;
KW Acetylation; ATP-binding; Cell membrane; Cytoplasm; Cytoplasmic vesicle;
KW Endocytosis; Exocytosis; Golgi apparatus; Kinase; Lipid metabolism;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT CHAIN 2..1685
FT /note="Phosphatidylinositol 4-phosphate 3-kinase C2 domain-
FT containing subunit alpha"
FT /id="PRO_0000088797"
FT DOMAIN 419..507
FT /note="PI3K-RBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00879"
FT DOMAIN 680..839
FT /note="C2 PI3K-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041,
FT ECO:0000255|PROSITE-ProRule:PRU00880"
FT DOMAIN 859..1035
FT /note="PIK helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00878"
FT DOMAIN 1103..1381
FT /note="PI3K/PI4K catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT DOMAIN 1420..1536
FT /note="PX"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00147"
FT DOMAIN 1554..1677
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT REGION 1..33
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..142
FT /note="Interaction with clathrin; sufficient to induce
FT clathrin assembly"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT REGION 41..60
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1109..1115
FT /note="G-loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1245..1253
FT /note="Catalytic loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1264..1290
FT /note="Activation loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1486..1491
FT /note="Interaction with PtdIns(4,5)P2-containing membranes"
FT /evidence="ECO:0000250|UniProtKB:Q61194"
FT MOTIF 1607..1618
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT COMPBIAS 17..33
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT MOD_RES 60
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT MOD_RES 108
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT MOD_RES 259
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT MOD_RES 327
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT MOD_RES 338
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT MOD_RES 628
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
FT MOD_RES 1551
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00443"
SQ SEQUENCE 1685 AA; 190466 MW; 2C48ED378DE0C2BD CRC64;
MAQISSNSGF KECPSSHPEP TRAKDVDKEE ALQMEAEALA KLQKDRQVTD NQRGFELSSS
TRKKAQVYNK QDYDLMVFPE SDSQKRALDI DVEKLTQAEL EKLLLDDSLE TRKTPVLPVT
PILSPSFSAQ LYFRPTIQRG QWPPGLSGPS TYALPSIYPS TYSKQAAFQN GFNPRMPTFP
STEPIYLSLP GQSPYFSYPL TPATPFHPQG SLPIYRPVVS PDMAKLFDKI ASTSEFLKNG
KARADLEITD SKVSNLQVSP KSEDISKFDW LDLDPLSKPK VDNVEVLDHE EEKNVSSLLA
KDPWDAVLLE ERSTANCHLE RKMNGKSLSV ATVTRSQSLN IRTTQLAKAH ISQKDPNGTS
SLPTGSSLLQ EVEVQNEEMA AFSRSITKLK TKFPYTNHHT NPGYLLSPVT AQRNICGENA
SVKVSIDIEG FQLPVTFTCD VSSTVEIIIM QALCWVHDDL NQVDVGSYVL KVCGQEEVLQ
NNHCLGSHEH IQNCRKWDTE IRLQLLTFSA MCQNLARTAE DDETPVDLNK HLYQIEKPYK
EAMTRHPVEE LLDSYHNQVE LALQIENQHR AVDQVIKAVR KICSALDGVE TLAITESVKK
LKRAVNLPRS KTADVASLFG GEDTSKSSTR GSLNPENPVQ VSINQLTAAI YDLLRLHANS
GRSPTDCAQS SKSVKEAWTT TEQLQFTIFA AHGISSNWVS NYEKYYLICS LSHNGKDLFK
PIQSKKVGTY KNFFYLIKWD ELIIFPIQIS QLPLESLLHL TLFGILNQSS GSSPDSNKQR
KGPEALGKVS LPLFDFKRFL TCGTKLLYLW TSSHTNSVPG AVTKKGYVME RIVLQVDFPS
PAFDIIYTTP QVDRSIIQQH NLETLENDVK GKLLDILHKD SSLGLSKEDK AFLWEKRYYC
FKHPNCLPKI LASAPNWKWV NLAKTYSLLH QWPALYPLIA LELLDSKFAD QEVRSLAVTW
IEAISDDELT DLLPQFVQAL KYEIYLNSSL VQFLLSRALG NIQIAHNLYW LLKDALHDVQ
FSTRYEHVLG ALLSVGGKRL REELRKQTKL VQLLGGVAEK VRQASGSARQ VVLQRSMERV
QSFFQKNKCR LPLKPSLVAK ELSIKSCSFF SSNAVPLKVT MVNADPMGEE INVMFKVGED
LRQDMLALQM IKIMDKIWLK EGLDLRMVIF KCLSTGRDRG MVELVPASDT LRKIQVEYGV
TGSFKDKPLA EWLRKYNPSE EEYEKASENF IYSCAGCCVA TYVLGICDRH NDNIMLRSTG
HMFHIDFGKF LGHAQMFGTF KRDRAPFVLT SDMAYVINGG EKPTIRFQLF VDLCCQAYNL
IRKQTNLFLN LLSLMIPSGL PELTSIQDLK YVRDALQPQT TDAEATIFFT RLIESSLGSI
ATKFNFLIHN LAQLRFSGLP SNDEPILSFS PKTYSFKQDG RIKEVSVFTY HKKYNPDKHY
IYVVRILREG QIEPSFVFRT FDEFQELHNK LSIIFPLWKL PGFPNRMVLG RTHIKDVAAK
RKIELNSYLQ SLMNASTDVA ECDLVCTFFH PLLRDEKAEG IARSADAGSF SPPTPGQIGG
AVKLSISYRN GTLFIMVMHT KDLVTEDGAD PNPYVKTYLL PDNHKTSKRK TKISRKTRNP
TFNEMLVYSG YSKETLRQRE LQLSVLSAES LRENFFLGGV TLPLKDFNLS KETVKWYQLT
AATYL
