BioPAX pathway converted from "Beclin-1 complex phosphorylates PtdIns" in the Reactome database. LEFT-TO-RIGHT 2.7.1.137 Beclin-1 complex phosphorylates PtdIns The Beclin-1 complex (ATG14:PIK3C3:PIK3R4:BECN1) is essential for autophagosome formation (Matsunaga et al. 2009, 2010). PIK3C3 (VPS34), the catalytic component of this complex, is a class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P). PIK3C3 is essential for the early stages of autophagy and colocalizes strongly with early autophagosome markers (Axe et al. 2008). The role of PI3P in autophagosome formation is to recruit WIPI2b (Dooley et al. 2014) a member of the WIPI family (Proikas-Cezanne et al. 2004, 2015, Polson et al. 2010). Authored: Jupe, Steve, 2015-02-02 Reviewed: Tooze, Sharon A, 2015-05-13 Reviewed: Klionsky, Daniel J, 2015-09-03 Edited: Jupe, Steve, 2015-05-13 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 cytosol GENE ONTOLOGY GO:0005829 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 79 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 Reactome http://www.reactome.org COMPOUND C00002 additional information MI MI:0361 PI Phosphatidyl 1D-myo-inositol 1-phosphatidyl-1D-myo-inositol Reactome DB_ID: 426639 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 1-phosphatidyl-1D-myo-inositol [ChEBI:16749] 1-phosphatidyl-1D-myo-inositol ChEBI CHEBI:16749 Reactome Database ID Release 79 426639 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426639 Reactome R-ALL-426639 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-426639.3 COMPOUND C01194 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 79 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 PI3P PtdIns3P phosphatidylinositol 3-phosphate Reactome DB_ID: 5676030 phosphatidylinositol 3-phosphate [ChEBI:26034] phosphatidylinositol 3-phosphate PI(3)P phosphatidylinositol 3-phosphates PtdIns3P ChEBI CHEBI:26034 Reactome Database ID Release 79 5676030 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676030 Reactome R-ALL-5676030 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5676030.3 ACTIVATION activeUnit: #Protein1 Beclin-1 complex ATG14:PIK3C3:PIK3R4:p-S15-BECN1 Bakor:Vps34:Vps15:p-Beclin-1 Autophagy-specific class III PI3K complex Reactome DB_ID: 5679242 VPS34 PIK3C3 PI3K class III Catalytic subunit Reactome DB_ID: 188011 UniProt:Q8NEB9 PIK3C3 PIK3C3 VPS34 FUNCTION Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. As part of PI3KC3-C1, promotes endoplasmic reticulum membrane curvature formation prior to vesicle budding (PubMed:32690950). Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123, PubMed:20208530). Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for transport from early to late endosomes (By similarity).SUBUNIT Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are: the PI3K complex I (PI3KC3-C1) containing ATG14, and the PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits such as RUBCN, SH3GLB1/Bif-1 and AMBRA1 (PubMed:7628435, PubMed:19050071, PubMed:20643123, PubMed:19270696, PubMed:23878393, PubMed:25490155). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with RAB7A in the presence of PIK3R4 (PubMed:14617358). Interacts with AMBRA1 (By similarity). Interacts with BECN1P1/BECN2 (PubMed:23954414). Interacts with SLAMF1(PubMed:22493499). May be a component of a complex composed of RAB5A (in GDP-bound form), DYN2 and PIK3C3 (By similarity). Interacts with NCKAP1L (PubMed:16417406). Interacts with ATG14; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with STEEP1; the interaction is STING1-dependent and required for trafficking of STING1 from the endoplasmic reticulum (PubMed:32690950).TISSUE SPECIFICITY Ubiquitously expressed, with a highest expression in skeletal muscle.SIMILARITY Belongs to the PI3/PI4-kinase family. Homo sapiens NCBI Taxonomy 9606 UniProt Q8NEB9 1 EQUAL 887 EQUAL Reactome Database ID Release 79 188011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188011 Reactome R-HSA-188011 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188011.1 1 Beclin-1 p-S15-BECN1 BECN1_HUMAN Reactome DB_ID: 5682391 UniProt:Q14457 BECN1 BECN1 GT197 FUNCTION Plays a central role in autophagy (PubMed:23184933, PubMed:28445460). Acts as core subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123, PubMed:20208530, PubMed:26783301). Essential for the formation of PI3KC3-C2 but not PI3KC3-C1 PI3K complex forms. Involved in endocytosis (PubMed:25275521). Protects against infection by a neurovirulent strain of Sindbis virus (PubMed:9765397). May play a role in antiviral host defense.FUNCTION Beclin-1-C 35 kDa localized to mitochondria can promote apoptosis; it induces the mitochondrial translocation of BAX and the release of proapoptotic factors.SUBUNIT A homodimeric form is proposed to exist; this metastable form readily transits to ATG14- or UVRAG-containing complexes with BECN1:UVRAG being more stable than BECN1:ATG14 (By similarity). Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are PI3K complex I (PI3KC3-C1) containing ATG14, and PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex (PubMed:18843052, PubMed:19050071, PubMed:19270696, PubMed:23878393, PubMed:25490155). Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1 and AMBRA1 (PubMed:20643123, PubMed:19270696). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with AMBRA1, GOPC, GRID2 (By similarity). Interacts with BCL2 and BCL2L1 isoform Bcl-X(L); the interaction inhibits BECN1 function in promoting autophagy by interfering with the formation of the PI3K complex (PubMed:9765397, PubMed:16179260, PubMed:17446862, PubMed:17337444, PubMed:17659302). Interacts with cytosolic HMGB1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy (PubMed:20819940). Interacts with USP10, USP13, VMP1, DAPK1, RAB39A (PubMed:19180116, PubMed:17724469, PubMed:17337444, PubMed:21962518, PubMed:24349490). Interacts with the poly-Gln domain of ATXN3; the interaction causes deubiquitination at Lys-402 and stabilizes BECN1 (PubMed:28445460). Interacts with SLAMF1 (PubMed:22493499). Interacts with TRIM5; the interaction causes activation of BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2 (PubMed:25127057). Interacts with active ULK1 (phosphorylated on 'Ser-317') and MEFV simultaneously (PubMed:26347139). Interacts with WDR81 and WDR91; negatively regulates the PI3 kinase/PI3K activity associated with endosomal membranes (PubMed:26783301). Interacts with LAPTM4B; competes with EGFR for LAPTM4B binding; regulates EGFR activity (PubMed:28479384). Interacts with TRIM50 (PubMed:29604308). Interacts with TRIM16. Interacts with ATG14; this interaction is increased in the absence of TMEM39A (PubMed:31806350).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein TRS1.SUBUNIT (Microbial infection) Interacts with murine gammaherpesvirus 68 M11.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 (HHV-1) protein ICP34.5; this interaction antagonizes the host autophagy response.TISSUE SPECIFICITY Ubiquitous.DOMAIN The coiled coil domain can form antiparallel homodimers and mediates dimerization with the coiled coil domains of ATG14 or UVRAG involved in the formation of PI3K complexes.DOMAIN The C-terminal evolutionary conserved domain (ECD) contains poly-Gln-binding domains such as the ATXN3 poly-Gln motif, consistent with structural docking models revealing two highly scored poly-Gln-binding pockets in the ECD (PubMed:28445460). As some binding is observed with BECN1 lacking the ECD, other domains of BECN1 may also interact with ATXN3 (PubMed:28445460).PTM Phosphorylation at Thr-119 by DAPK1 reduces its interaction with BCL2 and BCL2L1 and promotes induction of autophagy (PubMed:19180116). In response to autophagic stimuli, phosphorylated at serine residues by AMPK in an ATG14-dependent manner, and this phosphorylation is critical for maximally efficient autophagy (PubMed:23878393).PTM Polyubiquitinated by NEDD4, both with 'Lys-11'- and 'Lys-63'-linkages (PubMed:21936852). 'Lys-11'-linked polyubiquitination leads to degradation and is enhanced when the stabilizing interaction partner VPS34 is depleted (PubMed:21936852). Deubiquitinated by USP10 and USP13, leading to stabilize the PIK3C3/VPS34-containing complexes (PubMed:21962518). Polyubiquitinated at Lys-402 with 'Lys-48'-linkages (PubMed:28445460). 'Lys-48'-linked polyubiquitination of Lys-402 leads to degradation (PubMed:28445460). Deubiquitinated by ATXN3, leading to stabilization (PubMed:28445460).PTM Proteolytically processed by caspases including CASP8 and CASP3; the C-terminal fragments lack autophagy-inducing capacity and are proposed to induce apoptosis. Thus the cleavage is proposed to be an determinant to switch from autophagy to apoptosis pathways affecting cellular homeostasis including viral infections and survival of tumor cells.MISCELLANEOUS Expanded poly-Gln tracts inhibit ATXN3-BECN1 interaction, decrease BECN1 levels and impair starvation-induced autophagy (PubMed:28445460).SIMILARITY Belongs to the beclin family. UniProt Q14457 15 EQUAL O-phospho-L-serine MOD MOD:00046 1 EQUAL 450 EQUAL Reactome Database ID Release 79 5682391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682391 Reactome R-HSA-5682391 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682391.1 1 p150 PIK3R4 PI3K class III regulatory subunit PI3-kinase p150 subunit Vps15 Reactome DB_ID: 188010 UniProt:Q99570 PIK3R4 PIK3R4 VPS15 FUNCTION Regulatory subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123).SUBUNIT Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are PI3K complex I (PI3KC3-C1) containing ATG14, and PI3K complex II (PI3KC3-C2) containing UVRAG (PubMed:8999962, PubMed:19270696, PubMed:23878393, PubMed:25490155). PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex (PubMed:25490155). Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1, AMBRA1 and NRBF2 (PubMed:19270696, PubMed:20643123, PubMed:24785657). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with RAB7A in the presence of PIK3C3/VPS34 (PubMed:14617358). Interacts with NRBF2 (PubMed:24785657).TISSUE SPECIFICITY Ubiquitously expressed.PTM Myristoylated.PTM Probably autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. UniProt Q99570 2 EQUAL 1358 EQUAL Reactome Database ID Release 79 188010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188010 Reactome R-HSA-188010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188010.1 1 ATG14 Beclin 1-associated autophagy-related key regulator BAKOR_HUMAN Reactome DB_ID: 5679263 UniProt:Q6ZNE5 ATG14 ATG14 ATG14L KIAA0831 FUNCTION Required for both basal and inducible autophagy. Determines the localization of the autophagy-specific PI3-kinase complex PI3KC3-C1 (PubMed:18843052, PubMed:19050071). Plays a role in autophagosome formation and MAP1LC3/LC3 conjugation to phosphatidylethanolamine (PubMed:19270696, PubMed:20713597). Promotes BECN1 translocation from the trans-Golgi network to autophagosomes (PubMed:20713597). Enhances PIK3C3 activity in a BECN1-dependent manner. Essential for the autophagy-dependent phosphorylation of BECN1 (PubMed:23878393). Stimulates the phosphorylation of BECN1, but suppresses the phosphorylation PIK3C3 by AMPK (PubMed:23878393). Binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion (PubMed:25686604). Modulates the hepatic lipid metabolism (By similarity).SUBUNIT Forms homooligomers; homo-oligomerization is essential for the roles in membrane tethering and enhancement of SNARE-mediated fusion (PubMed:25686604). Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex I (PI3KC3-C1) in which the core composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 is associated with ATG14 (PubMed:18843052, PubMed:19050071, PubMed:19270696, PubMed:22314358, PubMed:23878393). PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex (PubMed:25490155). PI3KC3-C1 can associate with further regulatory subunits. Interacts with PIK3CB (By similarity). Interacts (via coiled-coil domain) with BECN2 (via coiled-coil domain); this interaction is tighter than BECN2 self-association (PubMed:23954414, PubMed:28218432). Interacts with the STX17-SNAP29 binary t-SNARE complex (PubMed:25686604). Interacts with NRBF2 (By similarity). Interacts with PIK3C3 and BECN1; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with STEEP1; the interaction is required for trafficking of STING1 from the endoplasmic reticulum (PubMed:32690950).DOMAIN The coiled-coil domain is required for BECN1- and PIK3C3-binding and for autophagy.DOMAIN The final 80 residues in the C-terminus define a minimum required region for autophagosome binding called BATS.DOMAIN The N-terminal cysteine repeats are required for proper localization to the endoplasmic reticulum.SIMILARITY Belongs to the ATG14 family. UniProt Q6ZNE5 1 EQUAL 492 EQUAL Reactome Database ID Release 79 5679263 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5679263 Reactome R-HSA-5679263 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5679263.1 1 Reactome Database ID Release 79 5679242 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5679242 Reactome R-HSA-5679242 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5679242.1 GENE ONTOLOGY GO:0016303 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 79 5676051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676051 Reactome Database ID Release 79 5672012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5672012 Reactome R-HSA-5672012 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5672012.5 24954904 Pubmed 2014 WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1 Dooley, Hannah C Razi, Minoo Polson, Hannah E J Girardin, Stephen E Wilson, Michael I Tooze, Sharon A Mol. Cell 55:238-52 7628435 Pubmed 1995 A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system Volinia, S Dhand, R Vanhaesebroeck, B MacDougall, LK Stein, R Zvelebil, MJ Domin, J Panaretou, C Waterfield, MD EMBO J 14:3339-48 19270696 Pubmed 2009 Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages Matsunaga, Kohichi Saitoh, T Tabata, Keisuke Omori, Hiroko Satoh, T Kurotori, Naoki Maejima, Ikuko Shirahama-Noda, Kanae Ichimura, Tohru Isobe, Toshiaki Akira, Shizuo Noda, Takeshi Yoshimori, Tamotsu Nat. Cell Biol. 11:385-96 25568150 Pubmed 2015 WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome Proikas-Cezanne, Tassula Takacs, Zsuzsanna Dönnes, Pierre Kohlbacher, Oliver J. Cell. Sci. 128:207-217 20505359 Pubmed 2010 Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation Polson, Hannah E J de Lartigue, Jane Rigden, Daniel J Reedijk, Marco Urbé, Sylvie Clague, Michael J Tooze, Sharon A Autophagy 6:506-22 20713597 Pubmed 2010 Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L Matsunaga, Kohichi Morita, E Saitoh, T Akira, Shizuo Ktistakis, Nicholas T Izumi, Tetsuro Noda, Takeshi Yoshimori, Tamotsu J. Cell Biol. 190:511-21 18725538 Pubmed 2008 Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum Axe, Elizabeth L Walker, Simon A Manifava, Maria Chandra, Priya Roderick, H Llewelyn Habermann, A Griffiths, Gareth Ktistakis, Nicholas T J. Cell Biol. 182:685-701 15602573 Pubmed 2004 WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy Proikas-Cezanne, Tassula Waddell, Scott Gaugel, Anja Frickey, Tancred Lupas, Andrei Nordheim, Alfred Oncogene 23:9314-25