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   27-MAR-2024, entry version 114.
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; 10350at2759; -.
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:0046934; F:1-phosphatidylinositol-4,5-bisphosphate 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:0006897; P:endocytosis; ISS:UniProtKB.
DR   GO; GO:0006887; P:exocytosis; IEA:UniProtKB-KW.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   CDD; cd04012; C2A_PI3K_class_II; 1.
DR   CDD; cd08381; C2B_PI3K_class_II; 1.
DR   CDD; cd00869; PI3Ka_II; 1.
DR   CDD; cd05176; PI3Kc_C2_alpha; 1.
DR   CDD; cd07289; PX_PI3K_C2_alpha; 1.
DR   Gene3D; 2.60.40.150; C2 domain; 2.
DR   Gene3D; 1.10.1070.11; Phosphatidylinositol 3-/4-kinase, catalytic domain; 1.
DR   Gene3D; 1.25.40.70; Phosphatidylinositol 3-kinase, accessory domain (PIK); 1.
DR   Gene3D; 3.30.1520.10; Phox-like domain; 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:SF28; PHOSPHATIDYLINOSITOL 4-PHOSPHATE 3-KINASE C2 DOMAIN-CONTAINING SUBUNIT ALPHA; 1.
DR   PANTHER; PTHR10048; PHOSPHATIDYLINOSITOL KINASE; 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; ARM repeat; 1.
DR   SUPFAM; SSF49562; C2 domain (Calcium/lipid-binding domain, CaLB); 2.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   SUPFAM; SSF64268; PX domain; 1.
DR   SUPFAM; SSF54236; Ubiquitin-like; 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
//