UniProt functional annotation for O75385



	UniProt functional annotation for O75385

UniProt code: O75385.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Serine/threonine-protein kinase involved in autophagy in response to starvation (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:25040165). Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:25040165). Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR (PubMed:21795849). Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity (PubMed:21460634). May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences (PubMed:18936157). Plays a role early in neuronal differentiation and is required for granule cell axon formation (PubMed:11146101). May also phosphorylate SESN2 and SQSTM1 to regulate autophagy (PubMed:25040165). Phosphorylates FLCN, promoting autophagy (PubMed:25126726). {ECO:0000269|PubMed:11146101, ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:21460634, ECO:0000269|PubMed:21795849, ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25126726}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:25126726}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; Evidence={ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:25126726};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:18936157}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; Evidence={ECO:0000269|PubMed:18936157};

Activity regulation: Acetylation by KAT5/TIP60 stimulates the protein kinase activity. {ECO:0000250|UniProtKB:O70405}.

Subunit: Interacts with GABARAP and GABARAPL2 (PubMed:11146101). Interacts (via C-terminus) with ATG13 (PubMed:18936157). Part of a complex consisting of ATG13, ATG101, ULK1 and RB1CC1 (PubMed:19287211). Associates with the mammalian target of rapamycin complex 1 (mTORC1) through an interaction with RPTOR; the association depends on nutrient conditions and is reduced during starvation (PubMed:19211835, PubMed:21795849). Interacts with FEZ1; SCOC interferes with FEZ1- binding (PubMed:22354037). Interacts with TBC1D14 (PubMed:22613832). Interacts (phosphorylated form) with TRIM5 (PubMed:25127057). When phosphorylated at Ser-317, interacts with MEFV and BECN1 simultaneously (PubMed:26347139). Interacts with TRIM21 and IRF3, in the presence of TRIM21 (PubMed:26347139). Interacts with SESN2 (PubMed:25040165). Interacts with SQSTM1 (PubMed:25040165). Interacts with C9orf72 (PubMed:27334615). Interacts with WDR45 (PubMed:28561066). Interacts with ATG13; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with WIPI2 (PubMed:28890335). Interacts with ATP2A2 (PubMed:28890335). {ECO:0000269|PubMed:11146101, ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:19211835, ECO:0000269|PubMed:19287211, ECO:0000269|PubMed:19597335, ECO:0000269|PubMed:21795849, ECO:0000269|PubMed:22354037, ECO:0000269|PubMed:22613832, ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25127057, ECO:0000269|PubMed:26347139, ECO:0000269|PubMed:27334615, ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:28890335, ECO:0000269|PubMed:31806350}.

Subcellular location: Cytoplasm, cytosol {ECO:0000250}. Preautophagosomal structure {ECO:0000250}. Note=Under starvation conditions, is localized to puncate structures primarily representing the isolation membrane that sequesters a portion of the cytoplasm resulting in the formation of an autophagosome. {ECO:0000250}.

Tissue specificity: Ubiquitously expressed. Detected in the following adult tissues: skeletal muscle, heart, pancreas, brain, placenta, liver, kidney, and lung.

Ptm: Autophosphorylated. Phosphorylated under nutrient-rich conditions; dephosphorylated during starvation or following treatment with rapamycin. Under nutrient sufficiency, phosphorylated by MTOR/mTOR, disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). In response to nutrient limitation, phosphorylated and activated by AMPK, leading to activate autophagy. {ECO:0000250, ECO:0000269|PubMed:21205641}.

Ptm: Acetylated by KAT5/TIP60 under autophagy induction, promoting protein kinase activity. {ECO:0000250|UniProtKB:O70405}.

Similarity: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. APG1/unc-51/ULK1 subfamily. {ECO:0000255|PROSITE- ProRule:PRU00159}.

Sequence caution: Sequence=BAA34442.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Serine/threonine-protein kinase involved in autophagy in response to starvation (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:25040165). Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:25040165). Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR (PubMed:21795849). Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity (PubMed:21460634). May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences (PubMed:18936157). Plays a role early in neuronal differentiation and is required for granule cell axon formation (PubMed:11146101). May also phosphorylate SESN2 and SQSTM1 to regulate autophagy (PubMed:25040165). Phosphorylates FLCN, promoting autophagy (PubMed:25126726). {ECO:0000269\|PubMed:11146101, ECO:0000269\|PubMed:18936157, ECO:0000269\|PubMed:21460634, ECO:0000269\|PubMed:21795849, ECO:0000269\|PubMed:25040165, ECO:0000269\|PubMed:25126726}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:18936157, ECO:0000269\|PubMed:25126726}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; Evidence={ECO:0000269\|PubMed:18936157, ECO:0000269\|PubMed:25126726};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:18936157}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; Evidence={ECO:0000269\|PubMed:18936157};
Activity regulation:		Acetylation by KAT5/TIP60 stimulates the protein kinase activity. {ECO:0000250\|UniProtKB:O70405}.
Subunit:		Interacts with GABARAP and GABARAPL2 (PubMed:11146101). Interacts (via C-terminus) with ATG13 (PubMed:18936157). Part of a complex consisting of ATG13, ATG101, ULK1 and RB1CC1 (PubMed:19287211). Associates with the mammalian target of rapamycin complex 1 (mTORC1) through an interaction with RPTOR; the association depends on nutrient conditions and is reduced during starvation (PubMed:19211835, PubMed:21795849). Interacts with FEZ1; SCOC interferes with FEZ1- binding (PubMed:22354037). Interacts with TBC1D14 (PubMed:22613832). Interacts (phosphorylated form) with TRIM5 (PubMed:25127057). When phosphorylated at Ser-317, interacts with MEFV and BECN1 simultaneously (PubMed:26347139). Interacts with TRIM21 and IRF3, in the presence of TRIM21 (PubMed:26347139). Interacts with SESN2 (PubMed:25040165). Interacts with SQSTM1 (PubMed:25040165). Interacts with C9orf72 (PubMed:27334615). Interacts with WDR45 (PubMed:28561066). Interacts with ATG13; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with WIPI2 (PubMed:28890335). Interacts with ATP2A2 (PubMed:28890335). {ECO:0000269\|PubMed:11146101, ECO:0000269\|PubMed:18936157, ECO:0000269\|PubMed:19211835, ECO:0000269\|PubMed:19287211, ECO:0000269\|PubMed:19597335, ECO:0000269\|PubMed:21795849, ECO:0000269\|PubMed:22354037, ECO:0000269\|PubMed:22613832, ECO:0000269\|PubMed:25040165, ECO:0000269\|PubMed:25127057, ECO:0000269\|PubMed:26347139, ECO:0000269\|PubMed:27334615, ECO:0000269\|PubMed:28561066, ECO:0000269\|PubMed:28890335, ECO:0000269\|PubMed:31806350}.
Subcellular location:		Cytoplasm, cytosol {ECO:0000250}. Preautophagosomal structure {ECO:0000250}. Note=Under starvation conditions, is localized to puncate structures primarily representing the isolation membrane that sequesters a portion of the cytoplasm resulting in the formation of an autophagosome. {ECO:0000250}.
Tissue specificity:		Ubiquitously expressed. Detected in the following adult tissues: skeletal muscle, heart, pancreas, brain, placenta, liver, kidney, and lung.
Ptm:		Autophosphorylated. Phosphorylated under nutrient-rich conditions; dephosphorylated during starvation or following treatment with rapamycin. Under nutrient sufficiency, phosphorylated by MTOR/mTOR, disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). In response to nutrient limitation, phosphorylated and activated by AMPK, leading to activate autophagy. {ECO:0000250, ECO:0000269\|PubMed:21205641}.
Ptm:		Acetylated by KAT5/TIP60 under autophagy induction, promoting protein kinase activity. {ECO:0000250\|UniProtKB:O70405}.
Similarity:		Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. APG1/unc-51/ULK1 subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.
Sequence caution:		Sequence=BAA34442.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};