Macroautophagy (Homo sapiens)

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815, 1754, 181221, 291610283, 326122715, 1715, 17149, 311, 1123206221012236, 13, 3025726, 13, 3014241013, 26112phagophore assembly sitelysosomal lumencytosolautophagosomeendoplasmic reticulum lumenATG4A PRKAG2 ATG4D PRKAG2 MAP1LC3B ATG101 ATG101 GlyK130-ATG5 ATG14 SLC38A9 BECN1 MAP1LC3C MTMR3,MTMR14RB1CC1 p-T183-PRKAA1 GABARAPL3(1-117) LAMTOR4 SLC38A9 GABARAPL1 LAMTOR3 GABARAPL3 WIPI2 ULK1:ATG13:RB1CC1:ATG101GABARAPL2 ATPRRAGC MAP1LC3A MAP1LC3A(1-121) LAMTOR1 MTOR LAMTOR4 ATG12:ATG7:CysO572-ATG7:ATG10MAP1LC3A MLST8 ATG9B ATG12 LAMTOR4 ATG14 ATG5ATG101 ESCRT-IIIATG7 dimerPI(3,5)P2 WIPI2 PE RRAGD SLC38A9 ATG7 ATG7 GDP RB1CC1 LAMTOR3 WIPI1 LAMTOR5 GlyK166-ATG10 MTORC1withp-S722,S792-RPTOR:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101PIK3C3 WDR45B WDR45 MLST8 ATG7dimer:GlyK166-ATG10:ATG12ATG16L1 GlyK130-ATG5 GABARAPL1(1-117) ATG12 ATG16L1RPTOR ATG12 PIK3C3 AMP ATG101 ATG10:GlyK130-ATG5:ATG12AMBRA1:DYNLL1,DYNLL2ATG101 GABARAPL3 PRKAG1 MTOR GABARAP(1-117) MAP1LC3B GDP RRAGD RRAGB GTP RRAGD PRKAG1 RRAGC RRAGA LAMTOR4 LAMTOR5 ATG12 RB1CC1 PI3PADPATG101 LAMTOR1 RRAGB ATG12 p-T183-PRKAA1 MAP1LC3C RPTOR WIPI1,WIPI2,(WDR45,WDR45B):PI3PATG14 CHMP2A ATG7 PRKAB1 MLST8 p-S15-BECN1 GABARAPL1 PRKAB1 AMP MAP1LC3B(2-121) WDR45B MLST8 ATPATG13 MTORC1:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101DYNLL2 ATG3GABARAPL3 RPTOR MAP1LC3B ATG14:PIK3C3:PIK3R4:p-S15-BECN1AMBRA1 GDP ATPATG13 WIPI2:PI(3,5)P2GABARAPL1 MTOR p-T180,S317,S467,S556,S638,T575-ULK1 ATG12:GlyK166-ATG10AMP RB1CC1 ATG101 p-S15-BECN1 LAMTOR3 AMBRA1:DYNLL1,DYNLL2:BECN1 complexCHMP7 MAP1LC3C(1-147) PRKAG3 ATG4ATG101 ATG10 ATG14 p-AMPKheterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101ATG13 Beclin-1 complexp-T172-PRKAA2 PIK3C3 GABARAP ATG16L1complex:WIPI2:PI(3,5)P2ADPRRAGB ATG4D RB1CC1 CysO572-ATG7 GTP ATG7 ATG7 LAMTOR5 p-S722,S792-RPTOR ULK1 p-S758-ULK1 ATG4RRAGB ATG7 MAP1LC3A SLC38A9 CHMP4A ATG12PRKAG2 RRAGA PIK3C3 ADPp-AMPKheterotrimer:AMPCHMP4B MAP1LC3B DYNLL1 MAP1LC3A BECN1 PIK3C3 RRAGA MAP1LC3A RRAGA RHEB LAMTOR2 DYNLL2 p-RB1CC1 Selective autophagyRRAGD MAP1LC3C PIK3R4 ADPATG12 p-S317,467,556,638,T575-ULK1 DYNLL1 TSC1 ATG13 LAMTOR2 UVRAG PRKAB2 ULK1 p-S1387-TSC2 GABARAPL1 PRKAG2 ATG13 GABARAPL2 PIK3R4 GABARAPL3 MTORC1withp-S722,S792-RPTOR:Ragulator:Rag:RHEB:GTPBECN1 GlyK130-ATG5 CHMP3 LC3 familyprecursorsRRAGC MLST8 GlyK130-ATG5:ATG12RRAGC GABARAP LC3:CysO572-ATG7:ATG7AMP ATG4A RHEB MAP1LC3B ATG9A ATG9A,(ATG9B)GTP ATG10p-AMPKheterotrimer:AMP:ULK1:ATG13:RB1CC1:ATG101GABARAPL1 CHMP2B GTP ATG12 GlyK130-ATG5 PIK3R4 MAP1LC3B RRAGB RRAGA MLST8 p-AMPKheterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101LAMTOR2 RB1CC1 PRKAB2 CysO263-ATG3 RB1CC1 BECN1 complexRPTOR GDP ATG12 p-T172-PRKAA2 ATG13 GTP LAMTOR5 LC3 familyWIPI2 p-T172-PRKAA2 LAMTOR1 MTMR14 p-T172-PRKAA2 RHEB RRAGC DYNLL2 ATG4B DLCsPIK3R4 p-AMPKheterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:p-ATG13:p-RB1CC1:ATG101ATG3 CysO263-ATG3 ATG7 CysO572-ATG7 PRKAG2 MAP1LC3B RHEB GABARAPL1 GABARAP GABARAPL1 DYNLL1 ATG16L1 GABARAPL3 p-T183-PRKAA1 LAMTOR4 MTORC1:Ragulator:Rag:GNP:RHEB:GTPGABARAPL2 PRKAG1 BECN1 ATG101 WIPI1 GABARAPL2 LAMTOR1 PIK3C3 PE p-T183-PRKAA1 MAP1LC3A BECN1 p-ATG13 PICHMP6 SLC38A9 LC3:PEPIK3R4 CHMP4C MTOR ATG12:GlyK166-ATG10:ATG5ATPWIPI2 ATG101 ATG12:ATG7 dimerLAMTOR2 ATG16L1 complexGABARAP PECysO263-ATG3:LC3ATPLAMTOR2 ADPLAMTOR3 UVRAG complexGDP MTORC1:RHEB:GTP:ULK1:ATG13:RB1CC1:ATG101RRAGD PRKAG2 GABARAPL2 GABARAPL2 PRKAG1 PRKAB1 ATPMAP1LC3C GABARAP LC3:CysO263-ATG3:ATG7 dimerLC3:CysO572-ATG7:ATG7:ATG3LAMTOR5 p-S722,S792-RPTOR p-S758-ULK1:ATG13:RB1CC1:ATG101ATPPRKAB1 PRKAG3 p-T172-PRKAA2 CysO572-ATG7 RRAGC AMP MTORC1:Ragulator:Rag:GNP:RHEB:GDPLAMTOR1 p-S758-ULK1 PiGABARAPL2(1-117) PRKAB2 ATG14 MTOR LAMTOR3 ULK1 PI3PRB1CC1 RRAGA PRKAG1 PRKAG3 ATG4B AMP WIPI1,WIPI2,(WDR45,WDR45B)p-AMPKheterotrimer:AMP:p-S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101GABARAP GABARAPL3 PRKAG1 GlyK166-ATG10 ADPATPATG10 GABARAP GlyK166-ATG10 LAMTOR3 PRKAB1 BECN1complex:p-AMBRA1:DYNLL1,DYNLL2RB1CC1 LAMTOR2 DYNLL2 RHEB CysO572-ATG7 PRKAB1 p-AMBRA1ATG5 WDR45 p-T183-PRKAA1 MAP1LC3C GABARAPL2 GTP ATG4C RRAGD PRKAB2 PRKAB2 LAMTOR1 MTOR SLC38A9 MAP1LC3A ATG4C RRAGB ATG14:PIK3C3:PIK3R4:p-S15-BECN1PRKAG3 p-T172-PRKAA2 AMBRA1 RHEB MAP1LC3C LAMTOR4 LC3:PEPRKAB2 PI3P MTMR3 PI(3,5)P2 GABARAPL3 ATG12:ATG7:CysO572-ATG7MAP1LC3C ATG14 ATG7 ATG13 ATG12 p-T180,S317,S467,S556,S638,T575-ULK1 PIK3C3 ATG12 p-AMBRA1 TSC1:p-S1387-TSC2ADPPRKAG3 p-ATG13 p-T180,S317,S467,S556,S638,T575-ULK1 p-S758-ULK1 GDP LAMTOR5 ATG13 p-T183-PRKAA1 DYNLL1 PIK3R4 PIK3R4 AMBRA1PRKAG3 19


Description

Macroautophagy (hereafter referred to as autophagy) acts as a buffer against starvation by liberating building materials and energy sources from cellular components. It has additional roles in embryonic development, removal of apoptotic cells or organelles, antigen presentation, protection against toxins and as a degradation route for aggregate-prone proteins and infectious agents. The dysregulation of autophagy is involved in several human diseases, for example, Crohn's disease, cancer and neurodegeneration (Ravikumar et al. 2010).
Autophagy is highly conserved from yeast to humans; much of the machinery was first identified in yeast (see Klionsky et al. 2011). Initially, double-membraned cup-shaped structures called the isolation membrane or phagophore engulf portions of cytoplasm. The membranes fuse to form the autophagosome. In yeast cells, autophagosomes are formed at the phagophore assembly site (PAS) next to the vacuole. In mammals, autophagosomes appear throughout the cytoplasm then move along microtubules towards the microtubule-organising centre. This transport requires microtubules and the function of dynein motor proteins; depolymerization of microtubules or inhibition of dynein-dependent transport results in inhibition of autophagy (Kochl et al. 2006, Kimura et al. 2008). Autophagosomes fuse with lysosomes forming autolysosomes whose contents are degraded by lysosomal hydrolases (Mizushima et al. 2011).

The origins of the autophagosomal membrane and the incorporation of existing membrane material have been extensively debated. The endoplasmic reticulum (ER), mitochondria, mitochondria-associated ER membranes (MAMs), the Golgi, the plasma membrane and recycling endosomes have all been implicated in the nucleation of the isolation membrane and subsequent growth of the membrane (Lamb et al. 2013). Recently 3D tomographic imaging of isolation membranes has shown the cup-shaped isolation membrane tightly sandwiched between two sheets of ER and physically connected to the ER through a narrow membrane tube (Hayashi-Nishino et al. 2009, Yla-Anttila et al. 2009). This suggests that isolation membrane formation and elongation are guided by adjacent ER sheets, supporting the now prevalent 'ER cradle' model, which suggests that the isolation membrane arises from the ER (Hayashi-Nishino et al. 2009, Shibutani & Yoshimori 2014).

Autophagy is tightly regulated. The induction of autophagy in response to starvation is partly mediated by inactivation of the mammalian target of rapamycin (mTOR) (Noda & Ohsumi 1998) and activation of Jun N-terminal kinase (JNK), while energy loss induces autophagy by activation of AMP kinase (AMPK). Other pathways regulating autophagy are regulated by calcium, cyclic AMP, calpains and the inositol trisphosphate (IP3) receptor (Rubinsztein et al. 2012).

In mammals, two complexes cooperatively produce the isolation membrane. The ULK complex consists of ULK1/2, ATG13, (FIP200) and ATG101 (Alers et al. 2012). The PIK3C3-containing Beclin-1 complex consists of PIK3C3 (Vps34), BECN1 (Beclin-1, Atg6), PIK3R4 (p150, Vps15) and ATG14 (Barkor) (Matsunaga et al. 2009, Zhong et al. 2009). A similar complex where ATG14 is replaced by UVRAG functions later in autophagosome maturation and endocytic traffic (Itakura et al. 2008, Liang et al. 2008). Binding of KIAA0226 to this complex negatively regulates the maturation process (Matsunaga et al. 2009). The ULK and Beclin-1 complexes are recruited to specific autophagosome nucleation regions where they stimulate phosphatidylinositol-3-phosphate (PI3P) production and facilitate the elongation and initial membrane curvature of the phagophore membrane (Carlsson & Simonsen 2015).

The ULK complex is considered the most upstream component of the mammalian autophagy pathway (Itakura & Mizushima 2010), acting as an integrator of the autophagy signals downstream of mTORC1. It is not fully understood how ULK1 is modulated in response to environmental cues. Phosphorylation plays an essential role (Dunlop & Tee 2013) but it is not clear how phosphorylation regulates ULK1 activities (Ravikumar et al. 2010). ULK1 kinase activity is required for autophagy, but the substrate(s) of ULK1 that mediate its autophagic function are not certain. ULK1 may also have kinase-independent functions in autophagy (Wong et al. 2013).

PIK3C3 (Vps34) is a class III phosphatidylinositol 3-kinase that produces PI3P. It is essential for the early stages of autophagy and colocalizes strongly with early autophagosome markers (Axe et al. 2008). BECN1 binds several further proteins that affect autophagosome formation. Partners that induce autophagy include AMBRA1 (Fimia et al. 2007), UVRAG (Liang et al. 2006) and SH3GLB1 (Takahashi et al. 2007). Binding of BCL2 or BCL2L1 (Bcl-xL) inhibit autophagy (Pattingre et al. 2005, Ciechomska et al. 2009). The inositol 1,4,5-trisphosphate receptor complex that binds BCL2 also interacts with BECN1, inhibiting autophagy (Vincencio et al. 2009). CISD2 (Nutrient-deprivation autophagy factor-1, NAF1), a component in the IP3R complex, interacts with BCL2 at the ER and stabilizes the BCL2-BECN1 interaction (Chang et al. 2010). Starvation leads to activation of c-Jun NH2-terminal kinase-1 (JNK1), which results in the phosphorylation of BCL2 and BCL2L1, which release their binding to BECN1 and thus induces autophagosome formation (Wei et al. 2008).

AMBRA1 can simultaneously bind dynein and the Beclin-1 complex. During nutrient starvation, AMBRA1 is phosphorylated in a ULK1-dependent manner (Di Bartolomeo et al. 2010). This phosphorylation releases AMBRA1-associated Beclin-1 complexes from dynein and the microtubule network, freeing the complex to translocate to autophagy initiation sites (Di Bartolomeo et al. 2010).

A characteristic of this early phase of autophagosome formation is the formation of PI3P-enriched ER-associated structures called omegasomes (Axe et al. 2008) or cradles (Hayashi-Nishino et al. 2009). Omegasomes appear to concentrate at or near the connected mitochondria-associated ER membrane (Hamasaki et al. 2013). However, the phagophore also can incorporate existing material from other membrane sources such as ER exit sites (ERES), the ER-Golgi intermediate compartment (ERGIC), the Golgi, the plasma membrane and recycling endosomes (Carlsson & Simonsen 2015). Omegasomes lead to the formation of the isolation membrane or phagophore, which is thought to form de novo by an unknown mechanism (Simonsen & Stenmark 2008, Roberts & Ktistakis 2013). Phagophore expansion is probably mediated by membrane uptake from endomembranes and semi-autonomous organelles (Lamb et al. 2013, Shibutani & Yoshimori 2014).

ATG9 is a direct target of ULK1. In nutrient-rich conditions mammalian ATG9 is localized to the trans-Golgi network and endosomes (including early, late and recycling endosomes), whereas under starvation conditions it is localized to autophagosomes, in a process that is dependent on ULK1 (Young et al. 2006). ATG9 is believed to play a role in the delivery of vesicles derived from existing membranes to the expanding phagophore (Lamb et al. 2013). Yeast Atg9 forms a complex with Atg2 and Atg18 (Reggiori et al. 2004).

PI3P produced at the initiation site is sensed by WIPI2b, the mammalian homologue of Atg18 (Polson et al. 2010). WIPI2b then recruits Atg16L1 (Dooley et al. 2014). There are four WIPI proteins in mammalian cells (Proikas-Cezanne et al. 2015). They are all likely bind PI3P and be recruited to membranes but the function of WIPI1, 3 and 4 in autophagy is not yet clear. WIPI4 (WDR45) has been shown to bind Atg2 and to be involved in lipid droplet formation (Velikkakath et al. 2012); mutations in WIPI4 have been shown to cause a neurodegenerative disease (Saitsu et al. 2013).

The elongation of the membrane that will become the autophagosome is regulated by two ubiquitination-like reactions. First, the ubiquitin-like molecule ATG12 is conjugated to ATG5 by ATG7, which acts as an E1-like activating enzyme, and ATG10, which has a role similar to an E2 ubiquitin-conjugating enzyme. The ATG5:ATG12 complex then interacts non-covalently with ATG16L1. This complex associates with the forming autophagosome but dissociates from completed autophagosomes (Geng & Klionski 2008). The second ubiquitin-like reaction involves the conjugation of ubiquitin-like molecules of the LC3 family (Weidberg et al. 2010). LC3 proteins are conjugated through their C-terminal glycine residues with PE by the E1-like ATG7 and E2-like ATG3. This allows LC3 proteins to associate with the autophagosome membrane.

The ATG12:ATG5:ATG16L1 complex (Mizushima et al., 2011) acts as an E3 like enzyme for the conjugation of LC3 family proteins (mammalian homologues of yeast Atg8) to phosphatidylethanolamine (PE) (Hanada et al. 2007, Fujita et al. 2008). LC3 PE can be deconjugated by the protease ATG4 (Li et al. 2011, 2012). ATG4 is also responsible for priming LC3 proteins by cleaving the C terminus to expose a glycine residue (Kirisako et al, 2000, Scherz Shouval et al. 2007). LC3 proteins remain associated with autophagosomes until they fuse with lysosomes. The LC3-like proteins inside the resulting autolysosomes are degraded, while those on the cytoplasmic surface are delipidated and recycled. ATG5:ATG12:ATG16L1-positive LC3-negative vesicles represent pre-autophagosomal structures (pre-phagophores and possibly early phagophores), ATG5:ATG12:ATG16L1-positive LC3-positive structures can be considered to be phagophores, and ATG5:ATG12:ATG16L1-negative LC3-positive vesicles can be regarded as mature autophagosomes (Tandia et al. 2011).

Phagophore expansion is probably mediated by membrane uptake from endomembranes as well as from semiautonomous organelles (Lamb et al. 2013, Shibutani & Yoshimori 2014).

The mechanisms involved in the closure of the phagophore membrane are poorly understood. As the phagophore is a double-membraned structure, its closure involves the fusion of a narrow opening, a process that is distinct from other membrane fusion events (Carlsson & Simonsen 2015). The topology of the phagophore is similar to that of cytokinesis, viral budding or multivesicular body (MVB) formation. These processes rely on the Endosomal Sorting Complex Required for Transport (ESCRT) (Rusten et al. 2012). ESCRT and associated proteins facilitate membrane budding away from the cytosol and subsequent cleavage of the bud neck (Hurley & Hanson 2010). Several studies have shown that depletion of ESCRT subunits or the regulatory ATPase Vps4 causes an accumulation of autophagosomes (Filimonenko et al. 2007, Rusten et al. 2007) but it is not clear whether ESCRTs are required for autophagosome closure or for autophagosome to endosome fusion. UVRAG is also involved in the maturation step, recruiting proteins that bring about membrane fusion such as the class C Vps proteins, which activate Rab7 thereby promoting fusion with late endosomes and lysosomes (Liang et al. 2008). View original pathway at Reactome.

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Pathway is converted from Reactome ID: 1632852
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Reactome version: 74
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Reactome Author: Jupe, Steve

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114623view16:08, 25 January 2021ReactomeTeamReactome version 75
113071view11:13, 2 November 2020ReactomeTeamReactome version 74
112306view15:22, 9 October 2020ReactomeTeamReactome version 73
101204view11:10, 1 November 2018ReactomeTeamreactome version 66
100742view20:34, 31 October 2018ReactomeTeamreactome version 65
100286view19:11, 31 October 2018ReactomeTeamreactome version 64
99832view15:55, 31 October 2018ReactomeTeamreactome version 63
99389view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99086view12:39, 31 October 2018ReactomeTeamreactome version 62
93985view13:49, 16 August 2017ReactomeTeamreactome version 61
93589view11:28, 9 August 2017ReactomeTeamreactome version 61
87872view12:11, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86697view09:24, 11 July 2016ReactomeTeamreactome version 56
83138view10:07, 18 November 2015ReactomeTeamVersion54
81478view13:00, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
AMBRA1 ProteinQ9C0C7 (Uniprot-TrEMBL)
AMBRA1:DYNLL1,DYNLL2:BECN1 complexComplexR-HSA-5678311 (Reactome)
AMBRA1:DYNLL1,DYNLL2ComplexR-HSA-1632839 (Reactome)
AMBRA1ProteinQ9C0C7 (Uniprot-TrEMBL)
AMP MetaboliteCHEBI:16027 (ChEBI)
ATG10 ProteinQ9H0Y0 (Uniprot-TrEMBL)
ATG101 ProteinQ9BSB4 (Uniprot-TrEMBL)
ATG10:GlyK130-ATG5:ATG12ComplexR-HSA-5683578 (Reactome)
ATG10ProteinQ9H0Y0 (Uniprot-TrEMBL)
ATG12 ProteinO94817 (Uniprot-TrEMBL)
ATG12:ATG7 dimerComplexR-HSA-9020617 (Reactome)
ATG12:ATG7:CysO572-ATG7:ATG10ComplexR-HSA-5682888 (Reactome)
ATG12:ATG7:CysO572-ATG7ComplexR-HSA-5682668 (Reactome)
ATG12:GlyK166-ATG10:ATG5ComplexR-HSA-5682657 (Reactome)
ATG12:GlyK166-ATG10ComplexR-HSA-5682644 (Reactome)
ATG12ProteinO94817 (Uniprot-TrEMBL)
ATG13 ProteinO75143 (Uniprot-TrEMBL)
ATG14 ProteinQ6ZNE5 (Uniprot-TrEMBL)
ATG14:PIK3C3:PIK3R4:p-S15-BECN1ComplexR-HSA-5679242 (Reactome)
ATG14:PIK3C3:PIK3R4:p-S15-BECN1ComplexR-HSA-5682393 (Reactome)
ATG16L1 complex:WIPI2:PI(3,5)P2ComplexR-HSA-5679367 (Reactome)
ATG16L1 ProteinQ676U5 (Uniprot-TrEMBL)
ATG16L1 complexComplexR-HSA-5679262 (Reactome)
ATG16L1ProteinQ676U5 (Uniprot-TrEMBL)
ATG3 ProteinQ9NT62 (Uniprot-TrEMBL)
ATG3ProteinQ9NT62 (Uniprot-TrEMBL)
ATG4A ProteinQ8WYN0 (Uniprot-TrEMBL)
ATG4B ProteinQ9Y4P1 (Uniprot-TrEMBL)
ATG4C ProteinQ96DT6 (Uniprot-TrEMBL)
ATG4D ProteinQ86TL0 (Uniprot-TrEMBL)
ATG4ComplexR-HSA-5682664 (Reactome)
ATG5 ProteinQ9H1Y0 (Uniprot-TrEMBL)
ATG5ProteinQ9H1Y0 (Uniprot-TrEMBL)
ATG7 dimer:GlyK166-ATG10:ATG12ComplexR-HSA-5683577 (Reactome)
ATG7 ProteinO95352 (Uniprot-TrEMBL)
ATG7 dimerComplexR-HSA-5682892 (Reactome)
ATG9A ProteinQ7Z3C6 (Uniprot-TrEMBL)
ATG9A,(ATG9B)ComplexR-HSA-5671731 (Reactome)
ATG9B ProteinQ674R7 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
BECN1 complex:p-AMBRA1:DYNLL1,DYNLL2ComplexR-HSA-5678316 (Reactome)
BECN1 ProteinQ14457 (Uniprot-TrEMBL)
BECN1 complexComplexR-HSA-5676032 (Reactome)
Beclin-1 complexComplexR-HSA-5683379 (Reactome)
CHMP2A ProteinO43633 (Uniprot-TrEMBL)
CHMP2B ProteinQ9UQN3 (Uniprot-TrEMBL)
CHMP3 ProteinQ9Y3E7 (Uniprot-TrEMBL)
CHMP4A ProteinQ9BY43 (Uniprot-TrEMBL)
CHMP4B ProteinQ9H444 (Uniprot-TrEMBL)
CHMP4C ProteinQ96CF2 (Uniprot-TrEMBL)
CHMP6 ProteinQ96FZ7 (Uniprot-TrEMBL)
CHMP7 ProteinQ8WUX9 (Uniprot-TrEMBL)
CysO263-ATG3 ProteinQ9NT62 (Uniprot-TrEMBL)
CysO263-ATG3:LC3ComplexR-HSA-5682868 (Reactome)
CysO572-ATG7 ProteinO95352 (Uniprot-TrEMBL)
DLCsComplexR-HSA-2029105 (Reactome)
DYNLL1 ProteinP63167 (Uniprot-TrEMBL)
DYNLL2 ProteinQ96FJ2 (Uniprot-TrEMBL)
ESCRT-IIIComplexR-HSA-917723 (Reactome)
GABARAP ProteinO95166 (Uniprot-TrEMBL)
GABARAP(1-117) ProteinO95166 (Uniprot-TrEMBL)
GABARAPL1 ProteinQ9H0R8 (Uniprot-TrEMBL)
GABARAPL1(1-117) ProteinQ9H0R8 (Uniprot-TrEMBL)
GABARAPL2 ProteinP60520 (Uniprot-TrEMBL)
GABARAPL2(1-117) ProteinP60520 (Uniprot-TrEMBL)
GABARAPL3 ProteinQ9BY60 (Uniprot-TrEMBL)
GABARAPL3(1-117) ProteinQ9BY60 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
GlyK130-ATG5 ProteinQ9H1Y0 (Uniprot-TrEMBL)
GlyK130-ATG5:ATG12ComplexR-HSA-5683581 (Reactome)
GlyK166-ATG10 ProteinQ9H0Y0 (Uniprot-TrEMBL)
LAMTOR1 ProteinQ6IAA8 (Uniprot-TrEMBL)
LAMTOR2 ProteinQ9Y2Q5 (Uniprot-TrEMBL)
LAMTOR3 ProteinQ9UHA4 (Uniprot-TrEMBL)
LAMTOR4 ProteinQ0VGL1 (Uniprot-TrEMBL)
LAMTOR5 ProteinO43504 (Uniprot-TrEMBL)
LC3 family precursorsComplexR-HSA-5682661 (Reactome)
LC3 familyComplexR-HSA-5682694 (Reactome)
LC3:CysO263-ATG3:ATG7 dimerComplexR-HSA-5683596 (Reactome)
LC3:CysO572-ATG7:ATG7:ATG3ComplexR-HSA-5682867 (Reactome)
LC3:CysO572-ATG7:ATG7ComplexR-HSA-5682887 (Reactome)
LC3:PEComplexR-HSA-5682873 (Reactome)
LC3:PEComplexR-HSA-5683631 (Reactome)
MAP1LC3A ProteinQ9H492 (Uniprot-TrEMBL)
MAP1LC3A(1-121) ProteinQ9H492 (Uniprot-TrEMBL)
MAP1LC3B ProteinQ9GZQ8 (Uniprot-TrEMBL)
MAP1LC3B(2-121) ProteinQ9GZQ8 (Uniprot-TrEMBL)
MAP1LC3C ProteinQ9BXW4 (Uniprot-TrEMBL)
MAP1LC3C(1-147) ProteinQ9BXW4 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MTMR14 ProteinQ8NCE2 (Uniprot-TrEMBL)
MTMR3 ProteinQ13615 (Uniprot-TrEMBL)
MTMR3,MTMR14ComplexR-HSA-5682410 (Reactome)
MTOR ProteinP42345 (Uniprot-TrEMBL)
MTORC1

with

p-S722,S792-RPTOR:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101
ComplexR-HSA-5675791 (Reactome)
MTORC1

with

p-S722,S792-RPTOR:Ragulator:Rag:RHEB:GTP
ComplexR-HSA-5675700 (Reactome)
MTORC1:RHEB:GTP:ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5675639 (Reactome)
MTORC1:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5675701 (Reactome)
MTORC1:Ragulator:Rag:GNP:RHEB:GDPComplexR-HSA-5672139 (Reactome)
MTORC1:Ragulator:Rag:GNP:RHEB:GTPComplexR-HSA-5672812 (Reactome)
PE MetaboliteCHEBI:16038 (ChEBI)
PEMetaboliteCHEBI:16038 (ChEBI)
PI(3,5)P2 MetaboliteCHEBI:16851 (ChEBI)
PI3P MetaboliteCHEBI:17283 (ChEBI)
PI3PMetaboliteCHEBI:17283 (ChEBI)
PI3PMetaboliteCHEBI:26034 (ChEBI)
PIMetaboliteCHEBI:16749 (ChEBI)
PIK3C3 ProteinQ8NEB9 (Uniprot-TrEMBL)
PIK3R4 ProteinQ99570 (Uniprot-TrEMBL)
PRKAB1 ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 ProteinQ9UGI9 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
RB1CC1 ProteinQ8TDY2 (Uniprot-TrEMBL)
RHEB ProteinQ15382 (Uniprot-TrEMBL)
RPTOR ProteinQ8N122 (Uniprot-TrEMBL)
RRAGA ProteinQ7L523 (Uniprot-TrEMBL)
RRAGB ProteinQ5VZM2 (Uniprot-TrEMBL)
RRAGC ProteinQ9HB90 (Uniprot-TrEMBL)
RRAGD ProteinQ9NQL2 (Uniprot-TrEMBL)
SLC38A9 ProteinQ8NBW4 (Uniprot-TrEMBL)
Selective autophagyPathwayR-HSA-9663891 (Reactome) Autophagy can be a selective process where specific cargo (organelles/proteins) are targetted to degradation in the lysosome. In general, selective autophagy is initiated when a cellular signal tags the cargo organelle for degradation. Subsequently, cargo recognition proteins detect and recruit the organelle to interact directly or indirectly with Atg proteins forming the phagophore. The next steps involve formation of the autophagosome and fusion with the lysosome for degradation. Depending upon the organelle, different molecules are used to for the autophagy mechanism (Andling AL et al. 2017). Consequently, the different mechanisms are known by the organelle degraded such as mitophagy for mitochondia and lipophagy for lipid droplets.
TSC1 ProteinQ92574 (Uniprot-TrEMBL)
TSC1:p-S1387-TSC2ComplexR-HSA-5672337 (Reactome)
ULK1 ProteinO75385 (Uniprot-TrEMBL)
ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5666059 (Reactome)
UVRAG ProteinQ9P2Y5 (Uniprot-TrEMBL)
UVRAG complexComplexR-HSA-5683632 (Reactome) The PIK3C3-containing Beclin-1 complex consists of PIK3C3 (Vps34), BECN1 (Beclin-1, Atg6), PIK3R4 (p150, Vps15) and ATG14 (Barkor) (Matsunaga et al. 2009, Zhong et al. 2009). A similar complex where ATG14 is replaced by UVRAG functions later in autophagosome maturation and endocytic traffic (Itakura et al. 2008, Liang et al. 2008). Binding of KIAA0226 to this complex negatively regulates the maturation process (Matsunaga et al. 2009).
WDR45 ProteinQ9Y484 (Uniprot-TrEMBL)
WDR45B ProteinQ5MNZ6 (Uniprot-TrEMBL)
WIPI1 ProteinQ5MNZ9 (Uniprot-TrEMBL)
WIPI1,WIPI2,(WDR45,WDR45B):PI3PComplexR-HSA-5678302 (Reactome)
WIPI1,WIPI2,(WDR45,WDR45B)ComplexR-HSA-5678301 (Reactome)
WIPI2 ProteinQ9Y4P8 (Uniprot-TrEMBL)
WIPI2:PI(3,5)P2ComplexR-HSA-5692947 (Reactome)
p-AMBRA1 ProteinQ9C0C7 (Uniprot-TrEMBL)
p-AMBRA1ProteinQ9C0C7 (Uniprot-TrEMBL)
p-AMPK heterotrimer:AMP:ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5672141 (Reactome)
p-AMPK heterotrimer:AMP:p-S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5673748 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5675826 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5682402 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:p-ATG13:p-RB1CC1:ATG101ComplexR-HSA-5675837 (Reactome)
p-AMPK heterotrimer:AMPComplexR-HSA-380931 (Reactome)
p-ATG13 ProteinO75143 (Uniprot-TrEMBL)
p-RB1CC1 ProteinQ8TDY2 (Uniprot-TrEMBL)
p-S1387-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S15-BECN1 ProteinQ14457 (Uniprot-TrEMBL)
p-S317,467,556,638,T575-ULK1 ProteinO75385 (Uniprot-TrEMBL)
p-S722,S792-RPTOR ProteinQ8N122 (Uniprot-TrEMBL)
p-S758-ULK1 ProteinO75385 (Uniprot-TrEMBL)
p-S758-ULK1:ATG13:RB1CC1:ATG101ComplexR-HSA-5672130 (Reactome)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T180,S317,S467,S556,S638,T575-ULK1 ProteinO75385 (Uniprot-TrEMBL)
p-T183-PRKAA1 ProteinQ13131 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-1632857 (Reactome)
ADPArrowR-HSA-5665868 (Reactome)
ADPArrowR-HSA-5672008 (Reactome)
ADPArrowR-HSA-5672010 (Reactome)
ADPArrowR-HSA-5672012 (Reactome)
ADPArrowR-HSA-5673768 (Reactome)
ADPArrowR-HSA-5675868 (Reactome)
ADPArrowR-HSA-5679205 (Reactome)
AMBRA1:DYNLL1,DYNLL2:BECN1 complexArrowR-HSA-5678313 (Reactome)
AMBRA1:DYNLL1,DYNLL2:BECN1 complexR-HSA-1632857 (Reactome)
AMBRA1:DYNLL1,DYNLL2ArrowR-HSA-1632843 (Reactome)
AMBRA1:DYNLL1,DYNLL2R-HSA-5678313 (Reactome)
AMBRA1R-HSA-1632843 (Reactome)
ATG10:GlyK130-ATG5:ATG12ArrowR-HSA-5683588 (Reactome)
ATG10:GlyK130-ATG5:ATG12R-HSA-5682690 (Reactome)
ATG10ArrowR-HSA-5682690 (Reactome)
ATG10R-HSA-5682893 (Reactome)
ATG12:ATG7 dimerArrowR-HSA-5681980 (Reactome)
ATG12:ATG7 dimerR-HSA-9020616 (Reactome)
ATG12:ATG7:CysO572-ATG7:ATG10ArrowR-HSA-5682893 (Reactome)
ATG12:ATG7:CysO572-ATG7:ATG10R-HSA-5681999 (Reactome)
ATG12:ATG7:CysO572-ATG7:ATG10mim-catalysisR-HSA-5681999 (Reactome)
ATG12:ATG7:CysO572-ATG7ArrowR-HSA-9020616 (Reactome)
ATG12:ATG7:CysO572-ATG7R-HSA-5682893 (Reactome)
ATG12:GlyK166-ATG10:ATG5ArrowR-HSA-5682010 (Reactome)
ATG12:GlyK166-ATG10:ATG5R-HSA-5683588 (Reactome)
ATG12:GlyK166-ATG10ArrowR-HSA-5683583 (Reactome)
ATG12:GlyK166-ATG10R-HSA-5682010 (Reactome)
ATG12R-HSA-5681980 (Reactome)
ATG14:PIK3C3:PIK3R4:p-S15-BECN1ArrowR-HSA-5679205 (Reactome)
ATG14:PIK3C3:PIK3R4:p-S15-BECN1ArrowR-HSA-5682385 (Reactome)
ATG14:PIK3C3:PIK3R4:p-S15-BECN1R-HSA-5682385 (Reactome)
ATG14:PIK3C3:PIK3R4:p-S15-BECN1mim-catalysisR-HSA-5672012 (Reactome)
ATG16L1 complex:WIPI2:PI(3,5)P2ArrowR-HSA-5679255 (Reactome)
ATG16L1 complex:WIPI2:PI(3,5)P2mim-catalysisR-HSA-5678490 (Reactome)
ATG16L1 complexArrowR-HSA-5682012 (Reactome)
ATG16L1 complexR-HSA-5679255 (Reactome)
ATG16L1R-HSA-5682012 (Reactome)
ATG3ArrowR-HSA-5678490 (Reactome)
ATG3R-HSA-5682896 (Reactome)
ATG4mim-catalysisR-HSA-5681987 (Reactome)
ATG4mim-catalysisR-HSA-5682377 (Reactome)
ATG5R-HSA-5682010 (Reactome)
ATG7 dimer:GlyK166-ATG10:ATG12ArrowR-HSA-5681999 (Reactome)
ATG7 dimer:GlyK166-ATG10:ATG12R-HSA-5683583 (Reactome)
ATG7 dimerArrowR-HSA-5683583 (Reactome)
ATG7 dimerArrowR-HSA-5683593 (Reactome)
ATG7 dimerR-HSA-5681980 (Reactome)
ATG7 dimerR-HSA-5682011 (Reactome)
ATG9A,(ATG9B)ArrowR-HSA-5682385 (Reactome)
ATPR-HSA-1632857 (Reactome)
ATPR-HSA-5665868 (Reactome)
ATPR-HSA-5672008 (Reactome)
ATPR-HSA-5672010 (Reactome)
ATPR-HSA-5672012 (Reactome)
ATPR-HSA-5673768 (Reactome)
ATPR-HSA-5675868 (Reactome)
ATPR-HSA-5679205 (Reactome)
BECN1 complex:p-AMBRA1:DYNLL1,DYNLL2ArrowR-HSA-1632857 (Reactome)
BECN1 complex:p-AMBRA1:DYNLL1,DYNLL2R-HSA-5678315 (Reactome)
BECN1 complexArrowR-HSA-5678315 (Reactome)
BECN1 complexR-HSA-5678313 (Reactome)
BECN1 complexR-HSA-5679266 (Reactome)
Beclin-1 complexArrowR-HSA-5679266 (Reactome)
Beclin-1 complexR-HSA-5679205 (Reactome)
CysO263-ATG3:LC3ArrowR-HSA-5683593 (Reactome)
CysO263-ATG3:LC3R-HSA-5678490 (Reactome)
DLCsArrowR-HSA-5678315 (Reactome)
DLCsR-HSA-1632843 (Reactome)
ESCRT-IIIArrowR-HSA-5682388 (Reactome)
GlyK130-ATG5:ATG12ArrowR-HSA-5682690 (Reactome)
GlyK130-ATG5:ATG12R-HSA-5682012 (Reactome)
LC3 family precursorsR-HSA-5681987 (Reactome)
LC3 familyArrowR-HSA-5681987 (Reactome)
LC3 familyArrowR-HSA-5682377 (Reactome)
LC3 familyR-HSA-5682011 (Reactome)
LC3:CysO263-ATG3:ATG7 dimerArrowR-HSA-5681981 (Reactome)
LC3:CysO263-ATG3:ATG7 dimerR-HSA-5683593 (Reactome)
LC3:CysO572-ATG7:ATG7:ATG3ArrowR-HSA-5682896 (Reactome)
LC3:CysO572-ATG7:ATG7:ATG3R-HSA-5681981 (Reactome)
LC3:CysO572-ATG7:ATG7:ATG3mim-catalysisR-HSA-5681981 (Reactome)
LC3:CysO572-ATG7:ATG7ArrowR-HSA-5682011 (Reactome)
LC3:CysO572-ATG7:ATG7R-HSA-5682896 (Reactome)
LC3:PEArrowR-HSA-5678490 (Reactome)
LC3:PEArrowR-HSA-5682388 (Reactome)
LC3:PER-HSA-5682377 (Reactome)
LC3:PER-HSA-5682388 (Reactome)
MTMR3,MTMR14mim-catalysisR-HSA-5679206 (Reactome)
MTORC1

with

p-S722,S792-RPTOR:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101
ArrowR-HSA-5673768 (Reactome)
MTORC1

with

p-S722,S792-RPTOR:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101
R-HSA-5675790 (Reactome)
MTORC1

with

p-S722,S792-RPTOR:Ragulator:Rag:RHEB:GTP
ArrowR-HSA-5675790 (Reactome)
MTORC1:RHEB:GTP:ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5672817 (Reactome)
MTORC1:RHEB:GTP:ULK1:ATG13:RB1CC1:ATG101R-HSA-5672010 (Reactome)
MTORC1:RHEB:GTP:ULK1:ATG13:RB1CC1:ATG101mim-catalysisR-HSA-5672010 (Reactome)
MTORC1:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5672010 (Reactome)
MTORC1:RHEB:GTP:p-S758-ULK1:ATG13:RB1CC1:ATG101R-HSA-5673768 (Reactome)
MTORC1:Ragulator:Rag:GNP:RHEB:GDPArrowR-HSA-5672017 (Reactome)
MTORC1:Ragulator:Rag:GNP:RHEB:GTPR-HSA-5672017 (Reactome)
MTORC1:Ragulator:Rag:GNP:RHEB:GTPR-HSA-5672817 (Reactome)
MTORC1:Ragulator:Rag:GNP:RHEB:GTPmim-catalysisR-HSA-5672017 (Reactome)
PEArrowR-HSA-5682377 (Reactome)
PER-HSA-5678490 (Reactome)
PI3PArrowR-HSA-5672012 (Reactome)
PI3PR-HSA-5676229 (Reactome)
PI3PR-HSA-5679206 (Reactome)
PIArrowR-HSA-5679206 (Reactome)
PIR-HSA-5672012 (Reactome)
PiArrowR-HSA-5683925 (Reactome)
R-HSA-1632843 (Reactome) Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1) is anchored to microtubules through an interaction with dynein light chains 1 and 2, components of the dynein motor complex (Di Bartolomeo et al. 2010, Fimia et al. 2011).
R-HSA-1632857 (Reactome) Upon autophagy induction, ULK1 phosphorylates AMBRA1, which leads to the release of the Beclin-1 complex from the dynein motor complex (Di Bartolomeo et al. 2010).
R-HSA-5665868 (Reactome) In mammals, the ULK complex and the class III PI3 Kinase containing Beclin-1 complex jointly produce the phagophore membrane, the initial phase of autophagosome formation (Karanosis et al. 2013). It is not fully understood how ULK1 is modulated in response to environmental cues. Phosphorylation plays an essential role (Dunlop & Tee 2013), but it is not clear how phosphorylation of ULK1 (or ATG13) leads to regulation (Ravikumar et al. 2010). Nor is it clear what ULK1 kinase activity achieves, it is not required for formation of the core complex but may be important for the recruitment of other proteins or have a direct role in subsequent autophagosome formation. Exactly how the ULK1 complex transduces upstream signals to the downstream central autophagy pathway is unclear (Wong et al. 2013).

At least 30 phosphorylation sites have been identified on ULK1, although the majority of the responsible kinases and the functions of these phosphorylation events remain to be identified (Dorsey et al. 2009, Mack et al. 2012). During glucose starvation, several sites in human ULK1 (Ser-317 - Kim et al. 2011, S467, S556, T575, and S638 - Egan et al. 2011) are reported to be phosphorylated by AMPK and required for efficient autophagy (Kim et al. 2011, Egan et al. 2011). These five phosphorylations are annotated here.

ULK1 phosphorylation activates its kinase activity and leads to the inhibition of mTORC1, via phosphorylation of TSC2 and raptor (Kim et al. 2011). Two AMPK phosphorylation sites in ULK1 (S556 and T575) also appear to be 14-3-3 binding sites.
R-HSA-5672008 (Reactome) ULK1 phosphorylation activates its kinase activity and leads to the inhibition of mTORC1, via phosphorylation of TSC2 and raptor (Kim et al. 2011). Thr-180 in the activation loop of the catalytic centre of ULK1 is required for ULK1 kinase activity. This is suggested to be an autophosphorylation site, though the existence of an upstream kinase was not ruled out (Bach et al. 2011). A homologous site in yeast Atg1 is similarly required for kinase activity and suggested to be autophosphorylated (Yeh et al. 2010). Ser-1047 at the extreme C-terminal end of mouse ULK1 was proposed to be the main Ulk1 autophosphorylation site (Dorsey et al. 2009); the equivalent residue in human ULK1 is Thr-1046. ULK1-mediated phosphorylations of ATG13, FIP200, and ULK1 itself triggers autophagy (Mizushima et al. 2011).
R-HSA-5672010 (Reactome) Under nutrient-rich conditions, mTORC1 phosphorylates ULK1 on S758 (Kim et al. 2011, Egan et al. 2011). ULK1 phosphorylation correlates with autophagy inhibition and reduced ULK1 kinase activity (Jung et al. 2009, Ganley et al. 2009, Hosakawa et al. 2009). RB1CC1 (FIP200) is probably phosphorylated (Mizushima 2010). ULK1 phosphorylation on S758 disrupts interaction between ULK1 and AMPK, thereby preventing AMPK from phosphorylating ULK1 at activating sites (Jung et al. 2009, Kim et al. 2011, Egan et al. 2011). If phosphorylation of ULK1 complex components suppresses autophagy, activation might be expected to involve more than suppression of kinases such as mTORC1. The phosphatase inhibitor okadaic acid inhibits autophagy (Blankson et al. 1995) but the protein phosphatase(s) involved in ULK1 dephosphorylation are currently unknown (Wong et al. 2013).
R-HSA-5672011 (Reactome) The heterotrimeric AMPK kinase complex, when bound to AMP, binds strongly to the ULK1 kinase complex. Rapamycin increases the co-immunoprecipitation of AMPK and ULK1, suggesting that mTORC1 activity may regulate their association. mTORC1 phosphorylates ULK1 on S758 and this phosphorylation disrupts the interaction between ULK1 and AMPK (Kim et al. 2011, Egan et al. 2011), suggesting that under nutrient-rich conditions, active mTORC1 phosphorylates ULK1 to disrupt ULK1-AMPK interaction, which keeps ULK1 inactive.

When cellular energy is depleted, AMPK is activated and inhibits mTORC1 via phosphorylation of TSC2 and raptor, thereby, reducing S758 phosphorylation on ULK1. The S758 unphosphorylated ULK1 is able to associate with, and be activated by, AMPK (Egan et al. 2011). This coordinated phosphorylation of ULK1 by mTORC1 and AMPK may provide a mechanism by which cells can properly respond to a wide range of stimuli.

ULK1 was identified as the mammalian homologue of yeast Atg1 (Kuroyanagi et al. 1998, Chan et al. 2007). It functions in a complex with ATG13 (KIAA0652) and RB1CC1 (FIP200), this considered to be the core ULK complex, which associates with ATG101 (Hosokawa et al. 2009, Jung et al. 2009, Ganley et al. 2009, Mercer et al. 2009). ATG13 binds ULK1 (and ULK2), mediating the interaction with RB1CC1. All four components of this complex are essential for autophagy induction and predominantly localized to the cytosol, associating with the isolation membrane upon autophagy induction (Mizushima 2011). RB1CC1 in this complex can interact with many other proteins including Pyk2, FAK, TSC1, p53, ASK1, and TRAF2 (Gan & Guan 2008).
R-HSA-5672012 (Reactome) 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).
R-HSA-5672017 (Reactome) When cellular energy is depleted AMPK is activated and inhibits mTORC1 via phosphorylation of both TSC2 and Raptor (Gwinn et al. 2008). Phosphorylation of TSC2 increases its GAP activity on GTP-bound Rheb, enhancing the intrinsic GTPase activity of Rheb. Rheb converts its bound GTP to GDP which diminishes its stimulation of mTORC1 and thereby decreases mTORC1 kinase activity. AMPK also phosphorylates the mTORC1 component RPTOR (Raptor), which promotes its dissociation from the ULK1 complex. Both effects of AMPK lead to a reduction in S758 phosphorylation on ULK1 (Shang et al. 2011). The S758-unphosphorylated ULK1 is able to associate with, and be activated by, AMPK (Egan et al. 2011).

This event is positively regulated by the phosphorylation of the TSC complex by p-AMPK.
R-HSA-5672817 (Reactome) Under nutrient-rich conditions, the mTORC1 complex associates with the ULK complex (Mizushima 2010). Binding is mediated by Raptor, a substrate recognition subunit of mTORC1, and the PS domain of ULK1 (Hosokawa et al. 2009).

Active mTORC1 phosphorylates ULK1 Ser-758, which disrupts the interaction between ULK1 and AMPK, thereby maintaining ULK1 in an inactive state (Jung et al. 2009, Kim et al. 2011, Egan et al. 2011).

When cellular energy is depleted, AMPK is activated. It inhibits mTORC1 kinase activity via phosphorylation of both TSC2 and raptor (Gwinn et al. 2008). Inhibition of mTORC1 reduces S758 phosphorylation on ULK1 (Shang et al. 2011). The S758-unphosphorylated ULK1 is able to associate with, and be activated by, AMPK.
R-HSA-5673768 (Reactome) When cellular energy is depleted, the active AMPK complex (bound to AMPK, AMPK alpha phosphorylated on Thr-172 or Thr-174) phosphorylates the mTORC1 component RPTOR (Raptor) on Ser-722 and Ser-792. These phosphorylations are required for inhibition of mTORC1 activity in response to energy stress (Gwinn et al. 2008), and are believed to promote the dissociation of mTORC1 from the ULK1 complex (Wong et al. 2013). This reduces mTORC1 phosphorylation of ULK1 Ser-758, which consequently is able to associate with, and be activated by, AMPK (Egan et al. 2011). This coordinated phosphorylation of ULK1 by mTORC1 and AMPK may provide a mechanism by which cells can properly respond to a wide range of stimuli.
R-HSA-5675790 (Reactome) When cellular energy is depleted mTORC1 dissociates from the ULK1 complex (Hosakawa et al. 2009, Lee et al. 2010, Wong et al. 2013). The phosphorylation of RPTOR (Raptor) by AMPK promotes the dissociation of mTORC1 from the ULK1 complex, which leads to a reduction in S758 phosphorylation on ULK1 (Shang et al. 2011). The S758-unphosphorylated ULK1 is able to associate with, and be activated by, AMPK (Egan et al. 2011).
R-HSA-5675868 (Reactome) ULK1 (and ULK2) can phosphorylate both ATG13 and RB1CC1 (Hosakawa et al. 2009, Jung et al. 2009). Similarly Drosophila Atg1, the orthologue of ULK1, phosphorylates Drosophila Atg13 (Chang & Neufeld 2009). This phosphorylation is believed to be activating, opposing the inactivating phosphorylation of ATG13 by mTORC1 (Kamada et al. 2000, Hosakawa et al. 2009,Chang & Neufeld 2009, Jung et al. 2009) under conditions of nutrient sufficiency.
R-HSA-5676229 (Reactome) WD repeat domain phospoinositide-interacting protein 2 (WIPI2) was identified as the mammalian homologue of yeast Atg18 (Polson et al. 2010). Like the other WIPI proteins, it binds PI(3,5)P2 and is recruited to autophagosomal membranes, especially upon autophagy induction (Proikas-Cezanne et al. 2015). WIPI1, WIPI2 and WIPI4 all localize to the initiating autophagosome during autophagy (Proikas-Cezanne et al. 2007, Obara et al. 2008, Polson et al. 2010). WIPI2 has been found to specifically bind to ATG16L1, thereby recruiting the ATG12:ATG5:ATG16L1 complex that is required for LC3 lipidation (Dooley et al. 2014).
R-HSA-5678313 (Reactome) AMBRA1 (activating molecule in Beclin 1-related autophagy 1) is a mammalian scaffold protein that interacts with BECN1 (Beclin-1) in the Beclin-1 complex, which consists of BECN1, PIK3C3 (VPS34), PIK3R4 (VPS15) and ATG14. AMBRA1 promotes the interaction of BECN1 with PIK3C3 (Fimia et al. 2007). AMBRA1 can simultaneously bind dynein and the Beclin-1 complex. This anchors Beclin-1 complexes to the cytoplasmic microtubule network (Di Bartolomeo et al. 2010, Fimia et al. 2011). Downregulation of AMBRA1 increased staurosporine- or etoposide-induced apoptosis (Gu et al. 2014).
R-HSA-5678315 (Reactome) Phosphorylation of AMBRA1 by ULK1 leads to the release of the Beclin-1 complex from the dynein motor complex, allowing it to relocalize and initiate autophagosome nucleation (Di Bartolomeo et al. 2010).
R-HSA-5678490 (Reactome) The ATG16L1 complex (consisting of ATG12, ATG5 and ATG16L1) functions as an E3-like ligase, mediating the transfer of LC3 ubiquitin-like proteins from the E2-like enzyme ATG3 to phosphatidylethanolamine (PE) in the expanding membrane (Tanida et al. 2002, Hanada et al. 2007, Fujita et al. 2008, Sakoh-Nakatogawa et al. 2013). In this final step of LC3 lipidation, the C-terminal glycine of the LC3 protein is conjugated to PE through an amide bond (Ichimura et al. 2000). This results in the lipidation of LC3 proteins at the curved membrane forming the autophagosome (Carlsson & Simonsen 2015). The resulting lipid-conjugated LC3 proteins are sometimes referred to as LC3-II. In yeast the LC3 family is represented by one protein, Atg8, which has a C-terminal ubiquitin-like domain that is preceded by a short N-terminal extension. The human LC3 family has six members (Slobodkin & Elazar 2013). The microtubule-associated protein-1 light chain proteins MAP1LC3A, MAP1LC3B and MAP1LC3C typically have their names shortened respectively to LC3A, LC3B and LC3C. The remaining family members are the gamma-aminobutyric acid (GABA)-receptor-associated proteins GABARAP, GABARAPL1 and GABARAPL2. The biological relevance of this expansion of Atg8 proteins in higher eukaryotes is largely unknown (Slobodkin & Elazar 2013, Wild et al. 2014).

ATG3 has a membrane-curvature-sensing domain that may allow it to detect lipid-packing defects at the rim of the growing phagophore (Nath et al. 2014). This function would localize the lipidation reaction of LC3 or GABARAP to the highly-curved surface at the edge of the growing phagophore (Carlsson & Simonsen 2015).


Lipidation of LC3 proteins enables them to associate with the autophagosomal membrane as it expands (Weidberg et al. 2010, 2011, Mizushima et al. 2011, Lamb et al. 2013). ATG proteins dissociate from the isolation membrane before it closes to create an autophagosome, while LC3 proteins remain attached on what becomes the inner autophagosome membrane surface (Klionsky 2005). LC3 proteins are thought to play a role in the expansion and closure of the isolation membrane (Geng & Klionsky 2008, Fujita et al. 2008, Weidberg et al. 2010, 2011).
R-HSA-5679205 (Reactome) Following amino-acid starvation or mTOR inhibition, activated ULK1 phosphorylates BECN1 (Beclin-1) on Ser-15, thereby enhancing the activity of PIK3C3 (Vps34) in the Beclin-1 complex. This phosphorylation is required for full autophagic induction in mammals (Russell et al. 2013).
R-HSA-5679206 (Reactome) MTMR14 (Jumpy) and MTMR3 are PI3P phosphatases that negatively regulate autophagosome formation by dephosphorylating PI3P on phagophores and autophagosomes (Vergne et al. 2009, Taguchi-Atarashi et al. 2010, Vergne & Deretic 2010).
R-HSA-5679239 (Reactome) The ULK complex is recruited to the membrane site of phagophore nucleation, which is likely to be a pre-existing ER structure containing the multi-membrane spanning protein vacuole membrane protein 1 (VMP1) (Wirth et al. 2013, Koyama-Honda et al. 2013). This may be mediated by the C-terminal early autophagy targeting/tethering (EAT) domain of ULK1, which appears to be essential for recruitment to the site of phagophore nucleation (Chan et al. 2009, Ragusa et al. 2012). The N-terminus of the ATG13 component of the ULK complex may also contribute to membrane association as it can interact with acidic phospholipids and is required for the translocation of ATG13 to omegasomes (Karanasios et al. 2013).
R-HSA-5679255 (Reactome) WIPI2 can bind ATG16L in the ATG12:ATG5:ATG16L complex (Dooley et al. 2014). Subsequently, LC3 is conjugated to PE. Other uncharacterised mechanisms are believed to lead to the recruitment of the ATG16L1 complex at the point of autophagosome nucleation (Fujita et al. 2008, Carlsson & Simonsen 2015).
R-HSA-5679266 (Reactome) The Beclin-1 complex (ATG14:PIK3C3:PIK3R4:BECN1) associates with the endoplasmic reticulum (ER). The ATG14 component of the complex contains an ER-binding motif in its N-terminal domain, which appears to be essential for its function in autophagy and for the recruitment of the other Beclin-1 complex subunits to the site of phagophore formation (Matsunaga et al. 2010). N-terminal myristoylation of the PIK3R4 (p150) component may also anchor the Beclin-1 complex to the membrane (Panaretou et al. 1997, Wirth et al. 2013).
R-HSA-5681980 (Reactome) ATG7 acts as an E1-like enzyme for ATG12. It binds to and activates ATG12, allow its transfer to the E2-like ATG10. The amino-acid sequence of ATG12 ends with a glycine residue and does not require protease activation. ATG12 is activated by forming a thioester bond between its C-terminal Gly-140 and Cys-572 of ATG7 (Tanida et al. 1999, 2001). ATG7 has been shown to function in the form of a homodimer (Komatsu et al. 2001).
R-HSA-5681981 (Reactome) The activated LC3 protein is transferred to Cys-263 of ATG3 through a thioester bond (Ichimura et al. 2000, Tanida et al. 2002). Deletion mutagenesis, biochemical data and modeling suggest that recruitment of ATG3 to the ATG7 N-terminal FAP domain results in presentation of the ATG3 active site to the LC3-ATG7 thioester linkage from the opposing monomer in the ATG7 dimer (Tanida et al. 2012, Klionsky & Schulman 2014).
R-HSA-5681987 (Reactome) LC3 family proteins are processed by members of the ATG4 family, which remove a C-terminal residue to create an exposed C-terminal glycine (Kirisako et al. 2000, Tanida et al. 2004, Kabeya et al. 2004, Li et al. 2011). Processed LC3 proteins are sometimes referred to as LC3-I.
R-HSA-5681999 (Reactome) After activation, ATG12 is transferred to ATG10, which has a function that is analogous to an E2 enzyme (Shintani et al. 1999, Mizushima et al. 2002). ATG12 is transferred to the Cys-166 residue of ATG10 to form a thioester (Nemoto et al. 2003).
R-HSA-5682010 (Reactome) Nuclear magnetic resonance experiments, mutational analyses and crosslinking experiments show that ATG10 directly recognizes ATG5, binding it to place the side chain of ATG5 Lys-130 into an optimal orientation for its conjugation reaction with ATG12. ATG10 mediates the formation of the ATG12-ATG5 conjugate without a specific E3 enzyme (Yamaguchi et al. 2012).
R-HSA-5682011 (Reactome) The exposed LC3 protein C-terminal glycine forms a thioester bond with Cys-572 of ATG7, the same residue that participates in Atg12-Atg5 conjugation (Ichimura et al. 2000, Tanida et al. 2001, 2012).
R-HSA-5682012 (Reactome) ATG5 interacts with the small coiled-coil protein ATG16L1. The resulting ATG12-ATG5-ATG16L1 complex multimerizes through the oligomerization of ATG16L1 (Mizushima et al. 1999, 2003). The molecular weight of this multimeric complex suggests that it probably represents a tetramer of ATG12-ATG5-ATG16L1 (Kuma et al. 2002).
R-HSA-5682377 (Reactome) LC3:PE can be cleaved by ATG4 to release free LC3 (Kirisako et al. 2000, Kabeya et al. 2004, Kumanomidou et al. 2006, Satoo et al. 2009). ATG4 activity can be regulated by reactive oxygen species (ROS) (Scherz-Shouval et al. 2007) possibily to control release of LC3 from closed autophagosomes.
R-HSA-5682385 (Reactome) The first crucial event in autophagy is the induction or nucleation of the membrane that will become an autophagosome. This is also the least well understood step (Tooze & Yoshimuri 2010). Following PI3P enrichment of the membrane, the associated membrane is distinct from its precursor and considered to be a new cellular structure, called a phagophore or an isolation membrane. Though the origins of this membrane are not unequivocally established, recent studies using mammalian cells indicate a strong relationship between autophagosome formation sites and the ER. The PI3P binding protein DFCP1 is localized to the ER. In starved cells it forms dot-like structures on the ER. LC3-positive membranes were observed to emerge from these structures, and named omegasomes as they resembled the Greek letter omega (Axe et al. 2008). 3D tomographic imaging of isolation membranes have shown cup-shaped isolation membranes sandwiched between two sheets of ER, connected by a narrow membrane tube (Hayashi-Nishino et al. 2009, Yla-Anttila et al. 2009) suggesting that isolation membrane formation and elongation may be guided by the adjacent ER sheets (Shibutani & Yoshimuri 2014). ATG9 is a multi transmembrane spanning protein that may directly or indirectly participate in the formation of phagophore curvature, for example, by wedging of the membrane. It is also possible that ATG9 could function as a lipid transfer protein (Carlsson & Simonsen 2015). In nutrient rich conditions ATG9 localizes to the trans Golgi network and endosomes. Under starvation conditions it localizes to autophagosomes, in a process dependent on ULK1 (Young et al. 2006, Orsi et al. 2012). In yeast, the induction of autophagy leads to Atg9 rich Golgi derived vesicles 30 60nm in diameter (Mari et al. 2010, Yamamoto et al. 2012). These vesicles accumulate at the PAS in an Atg1 dependent manner, where Atg1 mediated phosphorylation of Atg9 facilitates the recruitment of Atg8 and Atg18 and subsequent phagophore expansion (Papinski et al. 2014). Vesicular or tubular trafficking from recycling endosomes might is thought to feed ATG9 and ATG16L1 positive membrane onto the growing phagophore in a process that appears to be regulated by the PX BAR protein SNX18 and by the RAB11 effector protein TBC1D14 in an opposite manner (Knævelsrud et al. 2013, Longatti et al. 2012, Puri et al. 2013).
R-HSA-5682388 (Reactome) The mechanisms involved in the closure of the phagophore into an enclosed autophagosome are poorly understood. As the phagophore is a double-membraned structure, closure involves the fusion of a narrow opening, a process that is distinct from other membrane fusion events (Carlsson & Simonsen 2015). The topology of the phagophore is similar to that of multivesicular bodies (MVB) that form by invagination of the early endosome membrane, viral budding and cytokinesis. All of these rely on the Endosomal Sorting Complex Required for Transport (ESCRT) (Rusten et al. 2012). The ESCRT and associated proteins facilitate membrane budding away from the cytosol and subsequent cleavage of the bud neck (Hurley & Hanson 2010). Several studies have shown that depletion of ESCRT subunits or the regulatory ATPase Vps4, causes an accumulation of autophagosomes (Filimonenko et al. 2007, Lee et al. 2007, Rusten et al. 2007). Several ESCRT subunits are PI3P-binding proteins. PI3P turnover by phosphatases mediates dissociation of the early core ATGs from the phagophore membrane, appears to regulate autophagosome size and is required for closure of the phagophore to form an autophagosome (Taguchi-Atarashi et al. 2010), which suggests that ESCRTs are recruited to closing phagophores through interactions with PI3P and that PI3P levels are regulated to control phagophore closure (Carlsson & Simonsen 2015).

UVRAG is also involved in the maturation step, recruiting proteins that bring about membrane fusion such as the class C Vps proteins, which activate Rab7 thereby promoting fusion with late endosomes and lysosomes (Liang et al. 2008).

In yeast cells autophagosomes are formed at the single phagophore assembly site (PAS) next to the vacuole. In mammals, autophagosomes are formed at multiple locations in the cytoplasm and moved bidirectionally along microtubules with a bias towards the microtubule organising center (MTOC) where lysosomes are enriched. This transport requires the function of dynein motor proteins (Kimura et al. 2008). Depolymerization of microtubules or inhibition of dynein-dependent transport results in inhibition of autophagy (Kochl et al. 2006).
R-HSA-5682690 (Reactome) ATG12 is transferred from ATG10, becoming conjugated to the target protein ATG5 at Lys-149 through an isopeptide bond (Mizushima et al. 1998). There is no E3-like enzyme involved in Atg12-Atg5 conjugation. Nuclear magnetic resonance experiments, mutational analyses, and crosslinking experiments showed that ATG10 directly recognizes ATG5, binding it to place the side chain of ATG5 Lys-145 into an optimal orientation for its conjugation reaction with ATG12, thereby enabling ATG10 to mediate the formation of the ATG12-ATG5 conjugate without a specific E3 enzyme (Yamaguchi et al. 2012).
R-HSA-5682893 (Reactome) The N-terminal domain of ATG7 recruits the E2-like protein ATG10 (Kaiser et al. 2012, Yamaguchi et al. 2012). Biochemical data and modeling suggest that recruitment of ATG10 to the ATG7 N-terminal domain results in presentation of the ATG10 active site to the ATG7-ATG12 thioester linkage from the opposing monomer in the ATG7 homodimer (Klionsky & Schulman 2014).
R-HSA-5682896 (Reactome) The ATG7 dimer with bound LC3 binds ATG3. Deletion mutagenesis, biochemical data and modeling suggest that recruitment of ATG3 to the ATG7 N-terminal FAP domain results in presentation of the ATG3 active site to the LC3-ATG7 thioester linkage from the opposing monomer in the ATG7 dimer (Tanida et al. 2012, Klionsky & Schulman 2014). The activated LC3 protein is transferred to the E2-like enzyme ATG3 through a thioester bond (Ichimura et al. 2000).
R-HSA-5683583 (Reactome) Following the transfer of ATG12 to ATG10 (Nemoto et al. 2003) the ATG10-ATG12 conjugate dissociates from ATG7.
R-HSA-5683588 (Reactome) ATG12 is transferred from ATG10, becoming conjugated to the ATG5 at Lys-130 through an isopeptide bond (Mizushima et al. 1998) that requires no E3-like enzyme. Nuclear magnetic resonance experiments, mutational analyses and crosslinking experiments show that ATG10 directly recognizes ATG5, binding it to place the side chain of ATG5 Lys-130 into an optimal orientation for its conjugation reaction with ATG12, thereby enabling ATG10 to mediate the formation of the ATG12-ATG5 conjugate without a specific E3 enzyme (Yamaguchi et al. 2012).
R-HSA-5683593 (Reactome) ATG7 dissociates from the ATG3-LC3 conjugate (Tanida et al. 2012, Klionsky & Schulman 2014).
R-HSA-5683925 (Reactome) Under starvation conditions ULK1 undergoes dephosphorylation, particularly at serine-639 and serine-758 (Shang et al. 2011). The S757 unphosphorylated ULK1 is able to associate with, and be activated by, AMPK (Egan et al. 2011). The protein phosphatase(s) involved in ULK1 dephosphorylation are currently unknown (Wong et al. 2013).
R-HSA-9020616 (Reactome) The amino-acid sequence of ATG12 ends with a glycine residue that does not require protease activation. ATG12 is activated by the formation of a thioester bond between the ATG12 C-terminal Gly-140 and Cys-572 of ATG7, which is functionally analogous to E1 enzymes in ubiquitination (Tanida et al. 1999, 2001). ATG7 has been shown to function in the form of a homodimer (Komatsu et al. 2001).
TSC1:p-S1387-TSC2ArrowR-HSA-5672017 (Reactome)
ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5683925 (Reactome)
ULK1:ATG13:RB1CC1:ATG101R-HSA-5672011 (Reactome)
ULK1:ATG13:RB1CC1:ATG101R-HSA-5672817 (Reactome)
UVRAG complexArrowR-HSA-5682388 (Reactome)
WIPI1,WIPI2,(WDR45,WDR45B):PI3PArrowR-HSA-5676229 (Reactome)
WIPI1,WIPI2,(WDR45,WDR45B)R-HSA-5676229 (Reactome)
WIPI2:PI(3,5)P2R-HSA-5679255 (Reactome)
p-AMBRA1ArrowR-HSA-5678315 (Reactome)
p-AMPK heterotrimer:AMP:ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5672011 (Reactome)
p-AMPK heterotrimer:AMP:ULK1:ATG13:RB1CC1:ATG101R-HSA-5665868 (Reactome)
p-AMPK heterotrimer:AMP:ULK1:ATG13:RB1CC1:ATG101mim-catalysisR-HSA-5665868 (Reactome)
p-AMPK heterotrimer:AMP:p-S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5665868 (Reactome)
p-AMPK heterotrimer:AMP:p-S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101R-HSA-5672008 (Reactome)
p-AMPK heterotrimer:AMP:p-S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101mim-catalysisR-HSA-5672008 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5672008 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5679239 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101R-HSA-5675868 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101mim-catalysisR-HSA-1632857 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101mim-catalysisR-HSA-5675868 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:ATG13:RB1CC1:ATG101mim-catalysisR-HSA-5679205 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:p-ATG13:p-RB1CC1:ATG101ArrowR-HSA-5675868 (Reactome)
p-AMPK heterotrimer:AMP:p-T180,S317,467,556,638,T575-ULK1:p-ATG13:p-RB1CC1:ATG101R-HSA-5679239 (Reactome)
p-AMPK heterotrimer:AMPR-HSA-5672011 (Reactome)
p-AMPK heterotrimer:AMPmim-catalysisR-HSA-5673768 (Reactome)
p-S758-ULK1:ATG13:RB1CC1:ATG101ArrowR-HSA-5675790 (Reactome)
p-S758-ULK1:ATG13:RB1CC1:ATG101R-HSA-5683925 (Reactome)
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