ID   PK3C3_HUMAN             Reviewed;         887 AA.
AC   Q8NEB9; Q15134;
DT   06-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-2002, sequence version 1.
DT   02-OCT-2024, entry version 196.
DE   RecName: Full=Phosphatidylinositol 3-kinase catalytic subunit type 3;
DE            Short=PI3-kinase type 3;
DE            Short=PI3K type 3;
DE            Short=PtdIns-3-kinase type 3;
DE            EC=2.7.1.137 {ECO:0000269|PubMed:7628435};
DE   AltName: Full=Phosphatidylinositol 3-kinase p100 subunit;
DE   AltName: Full=Phosphoinositide-3-kinase class 3;
DE   AltName: Full=hVps34;
GN   Name=PIK3C3 {ECO:0000312|HGNC:HGNC:8974}; Synonyms=VPS34 {ECO:0000305};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
RP   SUBUNIT, TISSUE SPECIFICITY, AND INTERACTION WITH PIK3R4.
RX   PubMed=7628435; DOI=10.1002/j.1460-2075.1995.tb07340.x;
RA   Volinia S., Dhand R., Vanhaesebroeck B., MacDougall L.K., Zvelebil M.J.,
RA   Domin J., Panaretou C., Waterfield M.D.;
RT   "A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-
RT   Vps15p protein sorting system.";
RL   EMBO J. 14:3339-3348(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Testis, and Uterus;
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 project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3] {ECO:0000305}
RP   FUNCTION, INTERACTION WITH RAB7A AND PIK3R4, AND SUBCELLULAR LOCATION.
RX   PubMed=14617358; DOI=10.1034/j.1600-0854.2003.00133.x;
RA   Stein M.P., Feng Y., Cooper K.L., Welford A.M., Wandinger-Ness A.;
RT   "Human VPS34 and p150 are Rab7 interacting partners.";
RL   Traffic 4:754-771(2003).
RN   [4]
RP   INTERACTION WITH NCKAP1L.
RX   PubMed=16417406; DOI=10.1371/journal.pbio.0040038;
RA   Weiner O.D., Rentel M.C., Ott A., Brown G.E., Jedrychowski M., Yaffe M.B.,
RA   Gygi S.P., Cantley L.C., Bourne H.R., Kirschner M.W.;
RT   "Hem-1 complexes are essential for Rac activation, actin polymerization,
RT   and myosin regulation during neutrophil chemotaxis.";
RL   PLoS Biol. 4:E38-E38(2006).
RN   [5]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [6]
RP   INTERACTION WITH BECN1 AND ATG14.
RX   PubMed=19050071; DOI=10.1073/pnas.0810452105;
RA   Sun Q., Fan W., Chen K., Ding X., Chen S., Zhong Q.;
RT   "Identification of Barkor as a mammalian autophagy-specific factor for
RT   Beclin 1 and class III phosphatidylinositol 3-kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:19211-19216(2008).
RN   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-261, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [8]
RP   FUNCTION, AND SUBUNIT.
RX   PubMed=20643123; DOI=10.1016/j.yexcr.2010.07.008;
RA   Thoresen S.B., Pedersen N.M., Liestol K., Stenmark H.;
RT   "A phosphatidylinositol 3-kinase class III sub-complex containing VPS15,
RT   VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative
RT   endocytic traffic.";
RL   Exp. Cell Res. 316:3368-3378(2010).
RN   [9]
RP   INTERACTION WITH BECN1; RUBCN; ATG14; PIK3R4 AND UVRAG.
RX   PubMed=19270696; DOI=10.1038/ncb1846;
RA   Matsunaga K., Saitoh T., Tabata K., Omori H., Satoh T., Kurotori N.,
RA   Maejima I., Shirahama-Noda K., Ichimura T., Isobe T., Akira S., Noda T.,
RA   Yoshimori T.;
RT   "Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate
RT   autophagy at different stages.";
RL   Nat. Cell Biol. 11:385-396(2009).
RN   [10]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=20208530; DOI=10.1038/ncb2036;
RA   Sagona A.P., Nezis I.P., Pedersen N.M., Liestol K., Poulton J.,
RA   Rusten T.E., Skotheim R.I., Raiborg C., Stenmark H.;
RT   "PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of
RT   FYVE-CENT to the midbody.";
RL   Nat. Cell Biol. 12:362-371(2010).
RN   [11]
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., Buerckstuemmer T.,
RA   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   [12]
RP   INTERACTION WITH SLAMF1.
RX   PubMed=22493499; DOI=10.1074/jbc.m112.367060;
RA   Ma C., Wang N., Detre C., Wang G., O'Keeffe M., Terhorst C.;
RT   "Receptor signaling lymphocyte-activation molecule family 1 (Slamf1)
RT   regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting
RT   a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG)
RT   complex.";
RL   J. Biol. Chem. 287:18359-18365(2012).
RN   [13]
RP   INTERACTION WITH BECN1P1/BECN2.
RX   PubMed=23954414; DOI=10.1016/j.cell.2013.07.035;
RA   He C., Wei Y., Sun K., Li B., Dong X., Zou Z., Liu Y., Kinch L.N., Khan S.,
RA   Sinha S., Xavier R.J., Grishin N.V., Xiao G., Eskelinen E.L., Scherer P.E.,
RA   Whistler J.L., Levine B.;
RT   "Beclin 2 functions in autophagy, degradation of G protein-coupled
RT   receptors, and metabolism.";
RL   Cell 154:1085-1099(2013).
RN   [14]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-282, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [15]
RP   INTERACTION WITH BECN1.
RX   PubMed=23878393; DOI=10.1128/mcb.00079-13;
RA   Fogel A.I., Dlouhy B.J., Wang C., Ryu S.W., Neutzner A., Hasson S.A.,
RA   Sideris D.P., Abeliovich H., Youle R.J.;
RT   "Role of membrane association and Atg14-dependent phosphorylation in
RT   beclin-1-mediated autophagy.";
RL   Mol. Cell. Biol. 33:3675-3688(2013).
RN   [16]
RP   RECONSTITUTION OF THE PI3K COMPLEX I, AND ELECTRON MICROSCOPY OF THE PI3K
RP   COMPLEX I.
RX   PubMed=25490155; DOI=10.7554/elife.05115;
RA   Baskaran S., Carlson L.A., Stjepanovic G., Young L.N., Kim do J., Grob P.,
RA   Stanley R.E., Nogales E., Hurley J.H.;
RT   "Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase
RT   complex.";
RL   Elife 3:0-0(2014).
RN   [17]
RP   INTERACTION WITH ATG14.
RX   PubMed=31806350; DOI=10.1016/j.molcel.2019.10.035;
RA   Miao G., Zhang Y., Chen D., Zhang H.;
RT   "The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy
RT   by Controlling the Trafficking of the PtdIns(4)P Phosphatase SAC1.";
RL   Mol. Cell 0:0-0(2019).
RN   [18]
RP   FUNCTION, AND INTERACTION WITH STEEP1.
RX   PubMed=32690950; DOI=10.1038/s41590-020-0730-5;
RA   Zhang B.C., Nandakumar R., Reinert L.S., Huang J., Laustsen A., Gao Z.L.,
RA   Sun C.L., Jensen S.B., Troldborg A., Assil S., Berthelsen M.F.,
RA   Scavenius C., Zhang Y., Windross S.J., Olagnier D., Prabakaran T.,
RA   Bodda C., Narita R., Cai Y., Zhang C.G., Stenmark H., Doucet C.M., Noda T.,
RA   Guo Z., Goldbach-Mansky R., Hartmann R., Chen Z.J., Enghild J.J., Bak R.O.,
RA   Thomsen M.K., Paludan S.R.;
RT   "STEEP mediates STING ER exit and activation of signaling.";
RL   Nat. Immunol. 21:868-879(2020).
RN   [19]
RP   ERRATUM OF PUBMED:32690950.
RX   PubMed=32929276; DOI=10.1038/s41590-020-0803-5;
RA   Zhang B.C., Nandakumar R., Reinert L.S., Huang J., Laustsen A., Gao Z.L.,
RA   Sun C.L., Jensen S.B., Troldborg A., Assil S., Berthelsen M.F.,
RA   Scavenius C., Zhang Y., Windross S.J., Olagnier D., Prabakaran T.,
RA   Bodda C., Narita R., Cai Y., Zhang C.G., Stenmark H., Doucet C.M., Noda T.,
RA   Guo Z., Goldbach-Mansky R., Hartmann R., Chen Z.J., Enghild J.J., Bak R.O.,
RA   Thomsen M.K., Paludan S.R.;
RL   Nat. Immunol. 21:1468-1469(2020).
RN   [20]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=34320401; DOI=10.1016/j.celrep.2021.109479;
RA   Williams C.G., Jureka A.S., Silvas J.A., Nicolini A.M., Chvatal S.A.,
RA   Carlson-Stevermer J., Oki J., Holden K., Basler C.F.;
RT   "Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2
RT   replication.";
RL   Cell Rep. 36:109479-109479(2021).
RN   [21]
RP   INTERACTION WITH YWHAG.
RX   PubMed=33473107; DOI=10.1038/s41467-020-20780-2;
RA   Wang W., Li J., Tan J., Wang M., Yang J., Zhang Z.M., Li C.,
RA   Basnakian A.G., Tang H.W., Perrimon N., Zhou Q.;
RT   "Endonuclease G promotes autophagy by suppressing mTOR signaling and
RT   activating the DNA damage response.";
RL   Nat. Commun. 12:476-476(2021).
RN   [22]
RP   FUNCTION, UBIQUITINATION, AND DEUBIQUITINATION.
RX   PubMed=33637724; DOI=10.1038/s41467-021-21715-1;
RA   Chen Y.H., Huang T.Y., Lin Y.T., Lin S.Y., Li W.H., Hsiao H.J., Yan R.L.,
RA   Tang H.W., Shen Z.Q., Chen G.C., Wu K.P., Tsai T.F., Chen R.H.;
RT   "VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID
RT   regulates autophagy, proteostasis and liver metabolism.";
RL   Nat. Commun. 12:1322-1322(2021).
CC   -!- FUNCTION: Catalytic subunit of the PI3K complex that mediates formation
CC       of phosphatidylinositol 3-phosphate; different complex forms are
CC       believed to play a role in multiple membrane trafficking pathways:
CC       PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in
CC       maturation of autophagosomes and endocytosis (PubMed:14617358,
CC       PubMed:33637724, PubMed:7628435). As part of PI3KC3-C1, promotes
CC       endoplasmic reticulum membrane curvature formation prior to vesicle
CC       budding (PubMed:32690950). Involved in regulation of degradative
CC       endocytic trafficking and required for the abscission step in
CC       cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20208530,
CC       PubMed:20643123). Involved in the transport of lysosomal enzyme
CC       precursors to lysosomes (By similarity). Required for transport from
CC       early to late endosomes (By similarity). {ECO:0000250|UniProtKB:O88763,
CC       ECO:0000269|PubMed:14617358, ECO:0000269|PubMed:20208530,
CC       ECO:0000269|PubMed:20643123, ECO:0000269|PubMed:32690950,
CC       ECO:0000269|PubMed:33637724, ECO:0000269|PubMed:7628435}.
CC   -!- FUNCTION: (Microbial infection) Kinase activity is required for SARS
CC       coronavirus-2/SARS-CoV-2 replication. {ECO:0000269|PubMed:34320401}.
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:0000269|PubMed:7628435};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12710;
CC         Evidence={ECO:0000305|PubMed:7628435};
CC   -!- COFACTOR:
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000269|PubMed:7628435};
CC   -!- SUBUNIT: Component of the PI3K (PI3KC3/PI3K-III/class III
CC       phosphatidylinositol 3-kinase) complex the core of which is composed of
CC       the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1
CC       associating with additional regulatory/auxiliary subunits to form
CC       alternative complex forms. Alternative complex forms containing a
CC       fourth regulatory subunit in a mutually exclusive manner are: the PI3K
CC       complex I (PI3KC3-C1) containing ATG14, and the PI3K complex II
CC       (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped
CC       architecture with PIK3R4 serving as a bridge between PIK3C3 and the
CC       ATG14:BECN1 subcomplex. Both, PI3KC3-C1 and PI3KC3-C2, can associate
CC       with further regulatory subunits such as RUBCN, SH3GLB1/Bif-1 and
CC       AMBRA1 (PubMed:19050071, PubMed:19270696, PubMed:20643123,
CC       PubMed:23878393, PubMed:25490155, PubMed:7628435). PI3KC3-C1 probably
CC       associates with PIK3CB (By similarity). Interacts with RAB7A in the
CC       presence of PIK3R4 (PubMed:14617358). Interacts with AMBRA1 (By
CC       similarity). Interacts with BECN1P1/BECN2 (PubMed:23954414). Interacts
CC       with SLAMF1 (PubMed:22493499). May be a component of a complex composed
CC       of RAB5A (in GDP-bound form), DYN2 and PIK3C3 (By similarity).
CC       Interacts with NCKAP1L (PubMed:16417406). Interacts with ATG14; this
CC       interaction is increased in the absence of TMEM39A (PubMed:31806350).
CC       Interacts with STEEP1; the interaction is STING1-dependent and required
CC       for trafficking of STING1 from the endoplasmic reticulum
CC       (PubMed:32690950). Interacts with YWHAG (PubMed:33473107). Interacts
CC       with ARMC3 (By similarity). {ECO:0000250|UniProtKB:Q6PF93,
CC       ECO:0000250|UniProtKB:Q9TXI7, ECO:0000269|PubMed:14617358,
CC       ECO:0000269|PubMed:16417406, ECO:0000269|PubMed:19050071,
CC       ECO:0000269|PubMed:19270696, ECO:0000269|PubMed:20643123,
CC       ECO:0000269|PubMed:22493499, ECO:0000269|PubMed:23878393,
CC       ECO:0000269|PubMed:23954414, ECO:0000269|PubMed:25490155,
CC       ECO:0000269|PubMed:31806350, ECO:0000269|PubMed:32690950,
CC       ECO:0000269|PubMed:33473107, ECO:0000269|PubMed:7628435, ECO:0000305}.
CC   -!- INTERACTION:
CC       Q8NEB9; Q6ZNE5: ATG14; NbExp=31; IntAct=EBI-1056470, EBI-2690371;
CC       Q8NEB9; Q14457: BECN1; NbExp=43; IntAct=EBI-1056470, EBI-949378;
CC       Q8NEB9; Q96F24: NRBF2; NbExp=14; IntAct=EBI-1056470, EBI-2362014;
CC       Q8NEB9; Q92622: RUBCN; NbExp=9; IntAct=EBI-1056470, EBI-2952709;
CC       Q8NEB9; Q9P2Y5: UVRAG; NbExp=25; IntAct=EBI-1056470, EBI-2952704;
CC       Q8NEB9; Q17UT5: X; Xeno; NbExp=2; IntAct=EBI-1056470, EBI-15834514;
CC   -!- SUBCELLULAR LOCATION: Midbody {ECO:0000269|PubMed:20208530}. Late
CC       endosome {ECO:0000269|PubMed:14617358}. Cytoplasmic vesicle,
CC       autophagosome {ECO:0000305|PubMed:14617358}. Note=As component of the
CC       PI3K complex I localized to pre-autophagosome structures. As component
CC       of the PI3K complex II localized predominantly to endosomes
CC       (PubMed:14617358). Localizes also to discrete punctae along the ciliary
CC       axoneme and to the base of the ciliary axoneme (By similarity).
CC       {ECO:0000250|UniProtKB:Q6PF93, ECO:0000305|PubMed:14617358}.
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed, with a highest expression
CC       in skeletal muscle. {ECO:0000269|PubMed:7628435}.
CC   -!- PTM: Ubiquitinated via 'Lys-29'- and 'Lys-48'-linked ubiquitination by
CC       UBE3C, promoting its degradation (PubMed:33637724). Deubiquitination by
CC       ZRANB1/TRABID promotes its stabilization, leading to autophagosome
CC       maturation (PubMed:33637724). {ECO:0000269|PubMed:33637724}.
CC   -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. {ECO:0000255|PROSITE-
CC       ProRule:PRU00880}.
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DR   EMBL; Z46973; CAA87094.1; -; mRNA.
DR   EMBL; BC033004; AAH33004.1; -; mRNA.
DR   EMBL; BC053651; AAH53651.1; -; mRNA.
DR   CCDS; CCDS11920.1; -.
DR   PIR; S57219; S57219.
DR   RefSeq; NP_002638.2; NM_002647.3.
DR   PDB; 3IHY; X-ray; 2.80 A; A/B/C/D/E=282-879.
DR   PDB; 3LS8; X-ray; 2.25 A; A/B=268-879.
DR   PDB; 4OYS; X-ray; 2.90 A; A=282-879.
DR   PDB; 4PH4; X-ray; 2.80 A; B=293-887.
DR   PDB; 4UWF; X-ray; 2.99 A; A=282-879.
DR   PDB; 4UWG; X-ray; 2.70 A; A=282-879.
DR   PDB; 4UWH; X-ray; 1.93 A; A=282-879.
DR   PDB; 4UWK; X-ray; 2.83 A; A=282-879.
DR   PDB; 4UWL; X-ray; 2.80 A; A=282-879.
DR   PDB; 5ANL; X-ray; 2.70 A; A=282-879.
DR   PDB; 5ENN; X-ray; 2.70 A; A/B=293-887.
DR   PDB; 6HOG; X-ray; 1.26 A; A=244-258.
DR   PDB; 6HOH; X-ray; 2.25 A; A/B/C/D=244-258.
DR   PDB; 6I3U; X-ray; 2.09 A; A=268-879.
DR   PDB; 6YKG; X-ray; 3.12 A; AAA=268-879.
DR   PDB; 7BL1; EM; 9.80 A; BBB=1-887.
DR   PDB; 7RSJ; X-ray; 1.88 A; A=282-879.
DR   PDB; 7RSP; X-ray; 1.67 A; A/B=282-879.
DR   PDB; 7RSV; X-ray; 1.78 A; A/B=282-879.
DR   PDB; 8RXR; X-ray; 2.06 A; A/B=282-879.
DR   PDB; 8SOR; EM; 3.96 A; B=1-887.
DR   PDB; 8SRQ; EM; 6.20 A; X=4-277.
DR   PDBsum; 3IHY; -.
DR   PDBsum; 3LS8; -.
DR   PDBsum; 4OYS; -.
DR   PDBsum; 4PH4; -.
DR   PDBsum; 4UWF; -.
DR   PDBsum; 4UWG; -.
DR   PDBsum; 4UWH; -.
DR   PDBsum; 4UWK; -.
DR   PDBsum; 4UWL; -.
DR   PDBsum; 5ANL; -.
DR   PDBsum; 5ENN; -.
DR   PDBsum; 6HOG; -.
DR   PDBsum; 6HOH; -.
DR   PDBsum; 6I3U; -.
DR   PDBsum; 6YKG; -.
DR   PDBsum; 7BL1; -.
DR   PDBsum; 7RSJ; -.
DR   PDBsum; 7RSP; -.
DR   PDBsum; 7RSV; -.
DR   PDBsum; 8RXR; -.
DR   PDBsum; 8SOR; -.
DR   PDBsum; 8SRQ; -.
DR   AlphaFoldDB; Q8NEB9; -.
DR   EMDB; EMD-12214; -.
DR   EMDB; EMD-12237; -.
DR   EMDB; EMD-12238; -.
DR   EMDB; EMD-2846; -.
DR   EMDB; EMD-40669; -.
DR   EMDB; EMD-40738; -.
DR   SMR; Q8NEB9; -.
DR   BioGRID; 111307; 106.
DR   ComplexPortal; CPX-73; Phosphatidylinositol 3-kinase complex, class III, ATG14 variant.
DR   ComplexPortal; CPX-74; Phosphatidylinositol 3-kinase complex, class III, UVRAG variant.
DR   CORUM; Q8NEB9; -.
DR   DIP; DIP-42272N; -.
DR   IntAct; Q8NEB9; 59.
DR   MINT; Q8NEB9; -.
DR   STRING; 9606.ENSP00000262039; -.
DR   BindingDB; Q8NEB9; -.
DR   ChEMBL; CHEMBL1075165; -.
DR   DrugBank; DB11962; GSK-1059615.
DR   DrugBank; DB06836; N-(5-{4-Chloro-3-[(2-hydroxyethyl)sulfamoyl]phenyl}-4-methyl-1,3-thiazol-2-yl)acetamide.
DR   DrugCentral; Q8NEB9; -.
DR   GuidetoPHARMACOLOGY; 2152; -.
DR   SwissLipids; SLP:000000904; -.
DR   iPTMnet; Q8NEB9; -.
DR   MetOSite; Q8NEB9; -.
DR   PhosphoSitePlus; Q8NEB9; -.
DR   BioMuta; PIK3C3; -.
DR   DMDM; 74730233; -.
DR   jPOST; Q8NEB9; -.
DR   MassIVE; Q8NEB9; -.
DR   PaxDb; 9606-ENSP00000262039; -.
DR   PeptideAtlas; Q8NEB9; -.
DR   ProteomicsDB; 73147; -.
DR   Pumba; Q8NEB9; -.
DR   Antibodypedia; 22392; 1007 antibodies from 39 providers.
DR   DNASU; 5289; -.
DR   Ensembl; ENST00000262039.9; ENSP00000262039.3; ENSG00000078142.14.
DR   GeneID; 5289; -.
DR   KEGG; hsa:5289; -.
DR   MANE-Select; ENST00000262039.9; ENSP00000262039.3; NM_002647.4; NP_002638.2.
DR   UCSC; uc002lap.4; human.
DR   AGR; HGNC:8974; -.
DR   CTD; 5289; -.
DR   DisGeNET; 5289; -.
DR   GeneCards; PIK3C3; -.
DR   HGNC; HGNC:8974; PIK3C3.
DR   HPA; ENSG00000078142; Low tissue specificity.
DR   MIM; 602609; gene.
DR   neXtProt; NX_Q8NEB9; -.
DR   OpenTargets; ENSG00000078142; -.
DR   PharmGKB; PA33307; -.
DR   VEuPathDB; HostDB:ENSG00000078142; -.
DR   eggNOG; KOG0906; Eukaryota.
DR   GeneTree; ENSGT00940000156943; -.
DR   InParanoid; Q8NEB9; -.
DR   OrthoDB; 10350at2759; -.
DR   PhylomeDB; Q8NEB9; -.
DR   TreeFam; TF102032; -.
DR   BioCyc; MetaCyc:HS01275-MONOMER; -.
DR   BRENDA; 2.7.1.137; 2681.
DR   PathwayCommons; Q8NEB9; -.
DR   Reactome; R-HSA-109704; PI3K Cascade.
DR   Reactome; R-HSA-1632852; Macroautophagy.
DR   Reactome; R-HSA-1660514; Synthesis of PIPs at the Golgi membrane.
DR   Reactome; R-HSA-1660516; Synthesis of PIPs at the early endosome membrane.
DR   Reactome; R-HSA-1660517; Synthesis of PIPs at the late endosome membrane.
DR   Reactome; R-HSA-168138; Toll Like Receptor 9 (TLR9) Cascade.
DR   Reactome; R-HSA-5668599; RHO GTPases Activate NADPH Oxidases.
DR   Reactome; R-HSA-9679504; Translation of Replicase and Assembly of the Replication Transcription Complex.
DR   Reactome; R-HSA-9694676; Translation of Replicase and Assembly of the Replication Transcription Complex.
DR   Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR   Reactome; R-HSA-983170; Antigen Presentation: Folding, assembly and peptide loading of class I MHC.
DR   SignaLink; Q8NEB9; -.
DR   SIGNOR; Q8NEB9; -.
DR   BioGRID-ORCS; 5289; 596 hits in 1200 CRISPR screens.
DR   ChiTaRS; PIK3C3; human.
DR   EvolutionaryTrace; Q8NEB9; -.
DR   GeneWiki; PIK3C3; -.
DR   GenomeRNAi; 5289; -.
DR   Pharos; Q8NEB9; Tchem.
DR   PRO; PR:Q8NEB9; -.
DR   Proteomes; UP000005640; Chromosome 18.
DR   RNAct; Q8NEB9; protein.
DR   Bgee; ENSG00000078142; Expressed in calcaneal tendon and 202 other cell types or tissues.
DR   ExpressionAtlas; Q8NEB9; baseline and differential.
DR   GO; GO:0044754; C:autolysosome; IDA:MGI.
DR   GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0005930; C:axoneme; ISS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005768; C:endosome; IBA:GO_Central.
DR   GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0030496; C:midbody; IDA:UniProtKB.
DR   GO; GO:0005777; C:peroxisome; IBA:GO_Central.
DR   GO; GO:0030670; C:phagocytic vesicle membrane; TAS:Reactome.
DR   GO; GO:0000407; C:phagophore assembly site; IBA:GO_Central.
DR   GO; GO:0035032; C:phosphatidylinositol 3-kinase complex, class III; IPI:ComplexPortal.
DR   GO; GO:0034271; C:phosphatidylinositol 3-kinase complex, class III, type I; IBA:GO_Central.
DR   GO; GO:0034272; C:phosphatidylinositol 3-kinase complex, class III, type II; IBA:GO_Central.
DR   GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; IDA:UniProt.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0016301; F:kinase activity; IDA:MGI.
DR   GO; GO:0052742; F:phosphatidylinositol kinase activity; IDA:UniProt.
DR   GO; GO:0004672; F:protein kinase activity; IEA:Ensembl.
DR   GO; GO:0000045; P:autophagosome assembly; IDA:UniProt.
DR   GO; GO:0097352; P:autophagosome maturation; IDA:ComplexPortal.
DR   GO; GO:0006914; P:autophagy; IMP:MGI.
DR   GO; GO:0030242; P:autophagy of peroxisome; IBA:GO_Central.
DR   GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR   GO; GO:0042149; P:cellular response to glucose starvation; ISS:UniProtKB.
DR   GO; GO:0045022; P:early endosome to late endosome transport; IDA:ComplexPortal.
DR   GO; GO:0006897; P:endocytosis; IBA:GO_Central.
DR   GO; GO:0016236; P:macroautophagy; ISS:UniProtKB.
DR   GO; GO:0046854; P:phosphatidylinositol phosphate biosynthetic process; IDA:UniProt.
DR   GO; GO:0036092; P:phosphatidylinositol-3-phosphate biosynthetic process; IDA:ComplexPortal.
DR   GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IBA:GO_Central.
DR   GO; GO:0044829; P:positive regulation by host of viral genome replication; IDA:UniProtKB.
DR   GO; GO:0006497; P:protein lipidation; IMP:MGI.
DR   GO; GO:0034497; P:protein localization to phagophore assembly site; IEA:Ensembl.
DR   GO; GO:0006622; P:protein targeting to lysosome; NAS:ComplexPortal.
DR   GO; GO:0010506; P:regulation of autophagy; IDA:ComplexPortal.
DR   GO; GO:0032465; P:regulation of cytokinesis; IMP:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; IDA:ComplexPortal.
DR   CDD; cd08397; C2_PI3K_class_III; 1.
DR   CDD; cd00870; PI3Ka_III; 1.
DR   CDD; cd00896; PI3Kc_III; 1.
DR   Gene3D; 2.60.40.150; C2 domain; 1.
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   InterPro; IPR016024; ARM-type_fold.
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; IPR002420; PI3K-type_C2_dom.
DR   InterPro; IPR001263; PI3K_accessory_dom.
DR   InterPro; IPR042236; PI3K_accessory_sf.
DR   InterPro; IPR008290; PI3K_Vps34.
DR   InterPro; IPR015433; PI_Kinase.
DR   PANTHER; PTHR10048:SF7; PHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT TYPE 3; 1.
DR   PANTHER; PTHR10048; PHOSPHATIDYLINOSITOL KINASE; 1.
DR   Pfam; PF00454; PI3_PI4_kinase; 1.
DR   Pfam; PF00792; PI3K_C2; 1.
DR   Pfam; PF00613; PI3Ka; 1.
DR   PIRSF; PIRSF000587; PI3K_Vps34; 1.
DR   SMART; SM00142; PI3K_C2; 1.
DR   SMART; SM00145; PI3Ka; 1.
DR   SMART; SM00146; PI3Kc; 1.
DR   SUPFAM; SSF48371; ARM repeat; 1.
DR   SUPFAM; SSF49562; C2 domain (Calcium/lipid-binding domain, CaLB); 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 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; PS51545; PIK_HELICAL; 1.
PE   1: Evidence at protein level;
KW   3D-structure; ATP-binding; Autophagy; Cell cycle; Cell division;
KW   Cytoplasmic vesicle; Endosome; Kinase; Lipid metabolism; Manganese;
KW   Nucleotide-binding; Phosphoprotein; Proteomics identification;
KW   Reference proteome; Transferase; Ubl conjugation.
FT   CHAIN           1..887
FT                   /note="Phosphatidylinositol 3-kinase catalytic subunit type
FT                   3"
FT                   /id="PRO_0000088802"
FT   DOMAIN          35..184
FT                   /note="C2 PI3K-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00880"
FT   DOMAIN          283..520
FT                   /note="PIK helical"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00878"
FT   DOMAIN          605..871
FT                   /note="PI3K/PI4K catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT   REGION          149..170
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          447..467
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          611..617
FT                   /note="G-loop"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT   REGION          740..748
FT                   /note="Catalytic loop"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT   REGION          759..780
FT                   /note="Activation loop"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT   MOD_RES         163
FT                   /note="Phosphothreonine; by AMPK"
FT                   /evidence="ECO:0000250|UniProtKB:Q6PF93"
FT   MOD_RES         165
FT                   /note="Phosphoserine; by AMPK"
FT                   /evidence="ECO:0000250|UniProtKB:Q6PF93"
FT   MOD_RES         244
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O88763"
FT   MOD_RES         261
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19369195"
FT   MOD_RES         282
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   CONFLICT        36
FT                   /note="K -> N (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        70
FT                   /note="L -> S (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        136
FT                   /note="F -> S (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        158
FT                   /note="K -> N (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        208
FT                   /note="E -> V (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        219..220
FT                   /note="VE -> GG (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        262
FT                   /note="M -> L (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        272..274
FT                   /note="KLA -> NLP (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        289..292
FT                   /note="NAAT -> YPSP (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        297..298
FT                   /note="NI -> KN (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        305..308
FT                   /note="TKQL -> SKPP (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        318
FT                   /note="K -> E (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        327
FT                   /note="E -> D (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        333..338
FT                   /note="FLKCVN -> ILTSVI (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        344
FT                   /note="E -> G (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        350
FT                   /note="E -> A (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        356
FT                   /note="K -> N (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        367
FT                   /note="L -> I (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        397
FT                   /note="L -> S (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        428
FT                   /note="E -> G (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        484
FT                   /note="C -> S (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        750
FT                   /note="L -> V (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        826
FT                   /note="A -> P (in Ref. 1; CAA87094)"
FT                   /evidence="ECO:0000305"
FT   HELIX           275..278
FT                   /evidence="ECO:0007829|PDB:6I3U"
FT   HELIX           281..283
FT                   /evidence="ECO:0007829|PDB:6I3U"
FT   HELIX           290..301
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          304..306
FT                   /evidence="ECO:0007829|PDB:4UWG"
FT   HELIX           310..318
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           320..323
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           327..329
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           330..336
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           342..354
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           360..367
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           374..384
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           389..402
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           403..405
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           408..413
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           437..439
FT                   /evidence="ECO:0007829|PDB:4UWH"
FT   HELIX           442..444
FT                   /evidence="ECO:0007829|PDB:7RSJ"
FT   TURN            445..447
FT                   /evidence="ECO:0007829|PDB:7RSJ"
FT   HELIX           475..484
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           487..501
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           504..509
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           511..530
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           533..561
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           566..578
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   TURN            580..583
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          591..593
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          596..604
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           606..608
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          613..616
FT                   /evidence="ECO:0007829|PDB:6I3U"
FT   STRAND          619..625
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          630..638
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           642..660
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          672..676
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          679..683
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           690..697
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           700..707
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          711..713
FT                   /evidence="ECO:0007829|PDB:4UWH"
FT   HELIX           714..716
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           719..738
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          748..751
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          757..759
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          770..773
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           781..786
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   STRAND          790..792
FT                   /evidence="ECO:0007829|PDB:4UWF"
FT   HELIX           793..811
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           813..821
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   TURN            822..825
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           829..832
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           835..837
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           838..845
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   TURN            846..849
FT                   /evidence="ECO:0007829|PDB:7RSP"
FT   HELIX           852..868
FT                   /evidence="ECO:0007829|PDB:7RSP"
SQ   SEQUENCE   887 AA;  101549 MW;  1C03D97338E44976 CRC64;
     MGEAEKFHYI YSCDLDINVQ LKIGSLEGKR EQKSYKAVLE DPMLKFSGLY QETCSDLYVT
     CQVFAEGKPL ALPVRTSYKA FSTRWNWNEW LKLPVKYPDL PRNAQVALTI WDVYGPGKAV
     PVGGTTVSLF GKYGMFRQGM HDLKVWPNVE ADGSEPTKTP GRTSSTLSED QMSRLAKLTK
     AHRQGHMVKV DWLDRLTFRE IEMINESEKR SSNFMYLMVE FRCVKCDDKE YGIVYYEKDG
     DESSPILTSF ELVKVPDPQM SMENLVESKH HKLARSLRSG PSDHDLKPNA ATRDQLNIIV
     SYPPTKQLTY EEQDLVWKFR YYLTNQEKAL TKFLKCVNWD LPQEAKQALE LLGKWKPMDV
     EDSLELLSSH YTNPTVRRYA VARLRQADDE DLLMYLLQLV QALKYENFDD IKNGLEPTKK
     DSQSSVSENV SNSGINSAEI DSSQIITSPL PSVSSPPPAS KTKEVPDGEN LEQDLCTFLI
     SRACKNSTLA NYLYWYVIVE CEDQDTQQRD PKTHEMYLNV MRRFSQALLK GDKSVRVMRS
     LLAAQQTFVD RLVHLMKAVQ RESGNRKKKN ERLQALLGDN EKMNLSDVEL IPLPLEPQVK
     IRGIIPETAT LFKSALMPAQ LFFKTEDGGK YPVIFKHGDD LRQDQLILQI ISLMDKLLRK
     ENLDLKLTPY KVLATSTKHG FMQFIQSVPV AEVLDTEGSI QNFFRKYAPS ENGPNGISAE
     VMDTYVKSCA GYCVITYILG VGDRHLDNLL LTKTGKLFHI DFGYILGRDP KPLPPPMKLN
     KEMVEGMGGT QSEQYQEFRK QCYTAFLHLR RYSNLILNLF SLMVDANIPD IALEPDKTVK
     KVQDKFRLDL SDEEAVHYMQ SLIDESVHAL FAAVVEQIHK FAQYWRK
//