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Showing ULK1 — ATG1 is a alias.

ULK1

Serine/threonine-protein kinase ULK1 · UniProt O75385

Length
1050 aa
Mass
112.6 kDa
Annotated
2026-06-10
100 papers in source corpus 49 papers cited in narrative 49 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ULK1 is a serine/threonine kinase that functions as the apical initiator of autophagy, integrating nutrient and energy status to trigger autophagosome biogenesis (PMID:21258367, PMID:21205641). Its activity is reciprocally gated by upstream kinases: AMPK phosphorylates ULK1 at Ser317/Ser777 under glucose starvation to promote autophagy and mitophagy, while mTOR phosphorylates Ser757 under nutrient sufficiency to disrupt the ULK1–AMPK interaction and block activation (PMID:21258367, PMID:21205641). Once active, ULK1 nucleates and expands large ER-associated clusters required for autophagosome formation, with cluster expansion depending on ULK1 kinase activity and Vps34 (PMID:37774021). ULK1 propagates the autophagy signal by phosphorylating a broad substrate set: Beclin-1 (Ser14) to stimulate the ATG14L–VPS34 lipid kinase complex (PMID:23685627), FUNDC1 (Ser17) and BNIP3 (Ser17) at the mitochondrial surface to enhance LC3 binding and selective mitophagy (PMID:24671035, PMID:34654847), and ATG13 (PMID:35246531); it also controls Atg9 trafficking (PMID:16940348) and SNARE-dependent autophagosome–lysosome fusion by phosphorylating YKT6 to prevent premature bundling (PMID:36644903). Beyond canonical autophagy, ULK1 phosphorylates COPII components SEC23B (Ser186) and Sec23A to remodel ER-to-Golgi trafficking during autophagy (PMID:30596474, PMID:28486929), phosphorylates VCP/p97 to drive stress-granule disassembly (PMID:30979586), and acts in cell death and migration pathways via RIPK1 (PMID:32320653) and paxillin (PMID:37846507). ULK1 activity, localization, and abundance are tightly controlled by post-translational modification — arginine dimethylation by PRMT5 (reversed by KDM5C) that licenses activating autophosphorylation at Thr180 (PMID:35246531), palmitoylation by ZDHHC13 that drives translocation to autophagosome formation sites (PMID:39169022), and a network of E3 ligases and deubiquitinases (NEDD4L, TRIM27, TRAF3, BTRC, USP20, USP24) that set ULK1 protein levels (PMID:27932573, PMID:35670107, PMID:33213267, PMID:29487085). ULK1 also feeds back to inhibit mTORC1 by phosphorylating raptor (PMID:21795849). Mechanistic studies in yeast establish that the kinase (Atg1) is activated by FIP200/Atg11-mediated dimerization and activation-loop autophosphorylation, with ATG8/LC3-family binding through the LIR motif being required for full kinase activity (PMID:32909946, PMID:20953146, PMID:31208283).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 High

    Established the upstream signal that switches ULK1 on, answering how energy status is transduced to autophagy and mitochondrial homeostasis.

    Evidence Genetic analysis in mammalian liver and C. elegans with phospho-deficient ULK1 reconstitution

    PMID:21205641

    Open questions at the time
    • Did not map all activating sites
    • Did not resolve how phosphorylation alters ULK1 conformation or substrate selection
  2. 2011 High

    Resolved the reciprocal AMPK/mTOR phosphorylation logic and identified a ULK1-to-mTORC1 negative feedback loop, defining ULK1 as a bidirectional node coupling nutrient sensing to autophagy.

    Evidence In vitro kinase assays, site-specific mutagenesis, co-IP and epistasis in cells and mice; separate raptor phosphorylation study

    PMID:21258367 PMID:21795849

    Open questions at the time
    • Stoichiometry and timing of competing AMPK/mTOR inputs in vivo not resolved
    • raptor feedback significance under physiological autophagy unclear
  3. 2013 High

    Identified Beclin-1 Ser14 as a direct ULK1 substrate linking ULK1 activation to VPS34 lipid kinase activation, establishing the downstream PI3K-activating step.

    Evidence In vitro kinase assay, mutagenesis, cross-species epistasis, VPS34 lipid kinase assay

    PMID:23685627

    Open questions at the time
    • Did not establish spatial coordination of Beclin-1 phosphorylation with autophagosome nucleation
  4. 2014 High

    Placed ULK1 at the mitochondrial surface in selective mitophagy by identifying FUNDC1 Ser17 phosphorylation, explaining how ULK1 directs cargo-specific autophagy.

    Evidence Co-IP, in vitro kinase assay, rescue in ULK1-null cells, live imaging

    PMID:24671035

    Open questions at the time
    • Trigger for ULK1 translocation to mitochondria not fully defined
  5. 2018 High

    Extended ULK1 substrate range to COPII machinery (SEC23B), showing ULK1 reroutes secretory trafficking to support autophagic flux.

    Evidence In vitro kinase assay, MS site mapping, mutagenesis, subcellular fractionation

    PMID:30596474

    Open questions at the time
    • Reconciliation with opposing Sec23A regulation not addressed
    • Quantitative contribution to flux unclear
  6. 2019 High

    Defined cargo-localized, AMPK/mTOR-independent ULK1 activation via NDP52/FIP200/TBK1, and uncovered non-autophagy roles in stress-granule disassembly through VCP phosphorylation.

    Evidence CRISPR epistasis with chemically induced dimerization; in vitro kinase, VCP ATPase assay, mouse KO myopathy model

    PMID:30853401 PMID:30979586

    Open questions at the time
    • How focal activation bypasses canonical upstream kinases mechanistically unclear
    • Direct disease causality of ULK1/2-VCP axis not established in humans
  7. 2022 High

    Revealed that ULK1 activation is licensed by arginine methylation and gated by competing E3 ligase networks, defining oxygen- and ubiquitin-dependent control of ULK1 abundance and activity.

    Evidence In vitro methylation/ubiquitination assays, writer/eraser identification, mutagenesis, mouse KO

    PMID:35246531 PMID:35670107

    Open questions at the time
    • Crosstalk hierarchy among the many ULK1 PTMs not integrated
    • Physiological dominance of each modifier in different tissues unclear
  8. 2023 High

    Quantified ULK1 cluster formation at the ER as the physical basis of autophagosome initiation and showed kinase-dependent cluster expansion.

    Evidence Single-molecule PALM with endogenous tagging and pharmacological perturbation

    PMID:37774021

    Open questions at the time
    • Molecular driver of initial clustering (kinase-independent) unidentified
    • Link between cluster size and downstream Atg14/LC3 recruitment kinetics incomplete
  9. 2024 High

    Identified palmitoylation by ZDHHC13 as the membrane-targeting signal for ULK1 translocation to autophagosome formation sites, connecting lipid modification to autophagy initiation.

    Evidence Acyl-RAC assay, ZDHHC13 KO/KD, live imaging, in vitro kinase readout on ATG14L

    PMID:39169022

    Open questions at the time
    • Depalmitoylating enzyme and turnover dynamics not defined
    • Interplay with phosphorylation-dependent clustering unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dozens of ULK1 phosphorylation events, ubiquitin marks, methylation, and palmitoylation are temporally and spatially integrated to produce a single coherent autophagy decision remains unresolved.
  • No unified model ordering competing PTMs in time
  • Substrate selectivity determinants across autophagy vs non-autophagy functions undefined
  • Structural basis of human ULK1 activation not fully resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 3 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1
Pathway
R-HSA-9612973 Autophagy 6 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AMPKATG13FIP200/ATG11FUNDC1GABARAPMAP1LC3BRPTORVCP
Complex memberships
Atg1-Atg13-Atg17 complex (yeast)ULK1-ATG13-FIP200 complex

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 AMPK directly phosphorylates ULK1 at Ser317 and Ser777 to activate it under glucose starvation, promoting autophagy. Conversely, mTOR phosphorylates ULK1 at Ser757 under nutrient sufficiency, disrupting the interaction between ULK1 and AMPK and preventing ULK1 activation. This coordinated phosphorylation is required for autophagy induction. In vitro kinase assays, phospho-specific antibodies, mutagenesis, co-immunoprecipitation, genetic epistasis in cell lines and mouse models Nature cell biology High 21258367
2010 AMPK phosphorylates ULK1 (and ULK2), connecting energy sensing to autophagy and mitophagy. Loss of AMPK or ULK1 causes aberrant accumulation of the autophagy adaptor p62 and defective mitophagy; reconstitution with a ULK1 mutant that cannot be phosphorylated by AMPK reveals this phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. Genetic analysis in mammalian liver and C. elegans, biochemical reconstitution with phospho-deficient mutants, co-immunoprecipitation Science High 21205641
2013 Upon amino-acid starvation or mTOR inhibition, activated ULK1 phosphorylates Beclin-1 on Ser14, enhancing the activity of the ATG14L-containing VPS34 complex and promoting autophagic flux. This phosphorylation is required for full autophagic induction in mammals and C. elegans. In vitro kinase assay, site-directed mutagenesis, genetic epistasis in C. elegans and mammalian cells, VPS34 lipid kinase activity assay Nature cell biology High 23685627
2006 siRNA-mediated depletion of ULK1 inhibits starvation-induced redistribution of mammalian Atg9 from the trans-Golgi network to peripheral endosomal/autophagosomal membranes, placing ULK1 upstream of Atg9 trafficking in autophagy. siRNA knockdown, live-cell fluorescence imaging, immunofluorescence colocalization Journal of cell science Medium 16940348
2014 ULK1 translocates to fragmented mitochondria upon mitophagy induction by hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1 and phosphorylates it at Ser17, enhancing FUNDC1 binding to LC3. A ULK1-binding-deficient FUNDC1 mutant prevents ULK1 translocation and inhibits mitophagy; kinase-active ULK1 and phospho-mimicking FUNDC1 rescue mitophagy in ULK1-null cells. Co-immunoprecipitation, in vitro kinase assay, mutagenesis, rescue experiments in ULK1-null cells, live imaging EMBO reports High 24671035
2011 ULK1 binds raptor (a component of mTORC1) and induces its phosphorylation, inhibiting mTORC1 kinase activity and cell proliferation independently of Atg5 and TSC2. This identifies a negative feedback loop from ULK1 to mTORC1. Co-immunoprecipitation, in vitro kinase assay, ULK1 knockdown/overexpression, cell proliferation assays Autophagy Medium 21795849
2019 During selective autophagy, NDP52 localizes and activates the ULK1 complex at cargo through interaction with FIP200/ULK1, facilitated by TBK1. Ectopic tethering of ULK1 to cargo bypasses the need for autophagy receptors and TBK1. This focal activation of ULK1 occurs independently of AMPK and mTOR. Chemically inducible dimerization assays, CRISPR KO lines, genetic epistasis, co-immunoprecipitation Molecular cell High 30853401
2019 ULK1 and ULK2 localize to stress granules and phosphorylate VCP/p97, increasing VCP's ATPase activity and ability to disassemble stress granules. Disruption of ULK1/2 expression in mice causes a vacuolar myopathy with TDP-43-positive inclusions similar to that caused by VCP mutations. In vitro kinase assay, co-immunoprecipitation, mouse knockout model, biochemical VCP activity assay Molecular cell High 30979586
2016 The E3 ubiquitin ligase NEDD4L ubiquitylates ULK1 for proteasomal degradation during autophagy progression, down-regulating ULK1 protein levels. ULK1 mRNA continues to be transcribed during this period, and upon reactivation of mTOR-dependent protein synthesis, ULK1 levels are restored. This NEDD4L-ULK1 axis controls oscillatory activation of autophagy. Co-immunoprecipitation, ubiquitination assays, cycloheximide chase, mTOR inhibitor experiments, pulse-chase Journal of Cell Biology Medium 27932573
2018 ULK1 phosphorylates SEC23B at Ser186 upon starvation, preventing its interaction with FBXW5 (an F-box E3 ubiquitin ligase) and thus stabilizing SEC23B. Phosphorylated SEC23B associates with SEC24A/B and relocalizes to the ER-Golgi intermediate compartment, promoting autophagic flux. Co-immunoprecipitation, in vitro kinase assay, mass spectrometry, site-directed mutagenesis, subcellular fractionation/localization eLife High 30596474
2017 ULK1 phosphorylates Sec23A, a COPII vesicle coat component, inhibiting its interaction with Sec31A. This reduces ER-to-Golgi trafficking during autophagy induction. Phosphorylation sites Ser207, Ser312, and Thr405 on Sec23A were identified; Ser207 most faithfully recapitulates ULK1's regulatory effects. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, live-cell imaging of ERES BMC cell biology Medium 28486929
2021 ULK1 phosphorylates BNIP3 at Ser17 adjacent to its LIR motif, promoting BNIP3 interaction with LC3 and mitophagy. ULK1 also similarly phosphorylates BNIP3L at Ser35. Additionally, ULK1 interaction promotes BNIP3 protein stability by limiting its proteasomal turnover, dependent on an intact BH3 domain. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, cycloheximide chase, mitophagy flux assay Scientific reports Medium 34654847
2020 ULK1 phosphorylates Exo70, a component of the exocyst complex, inhibiting Exo70 homo-oligomerization and assembly into the exocyst complex, thereby suppressing breast cancer cell migration and invasion. ERK1/2 phosphorylates Exo70 upon growth factor stimulation, which in turn suppresses its phosphorylation by ULK1. In vitro kinase assay, co-immunoprecipitation, mutagenesis, cell migration/invasion assays Nature communications Medium 31913283
2019 GABARAP subfamily ATG8 proteins positively regulate ULK1 activity and autophagosome formation, while LC3 subfamily proteins negatively regulate ULK1 activity. Mutation of the LIR motif of endogenous ULK1 (disrupting ATG8-ULK1 interaction) drastically reduced ULK1 kinase activity, autophagic degradation, and phagophore formation. Similarly, disruption of ATG13-ATG8 interaction suppressed ULK1 activity. CRISPR/TALEN genome editing of LIR motif, ATG8 subfamily depletion, ULK1 kinase activity assays, autophagy flux assays Autophagy High 31208283
2022 PRMT5 catalyzes symmetrical dimethylation of ULK1 at Arg170 (R170me2s), a modification removed by KDM5C. Low oxygen decreases KDM5C activity, causing accumulation of ULK1 R170me2s. Dimethylation promotes ULK1 autophosphorylation at T180, a prerequisite for activation, leading to phosphorylation of Atg13 and Beclin1, autophagosome formation, and mitochondrial clearance. In vitro methylation assay, mass spectrometry, site-directed mutagenesis, co-immunoprecipitation, autophagy flux assays, cell proliferation under hypoxia Nature communications High 35246531
2021 GSK3B directly interacts with ULK1 and phosphorylates it at Ser405 and Ser415 within the GABARAP-interacting region upon insulin withdrawal. This phosphorylation facilitates ULK1 interaction with MAP1LC3B and GABARAPL1; phosphorylation-defective ULK1 mutants fail to interact with these ATG8 proteins and cannot induce autophagy flux. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, autophagy flux assays Experimental & molecular medicine Medium 33654220
2020 MAPK1/ERK2-MAPK3/ERK1 phosphorylates ULK1, triggering its interaction with the E3 ubiquitin ligase BTRC (β-TrCP) and subsequent K48-linked ubiquitination and proteasomal degradation of ULK1. This attenuates mitophagy and promotes breast cancer bone metastasis. Co-immunoprecipitation, ubiquitination assays, pharmacological inhibitors, in vitro kinase assay, cancer cell invasion assays Autophagy Medium 33213267
2023 ULK1 directly interacts with LDHA and phosphorylates it at Ser196 under nutrient deprivation, promoting lactate production. Lactate in turn mediates Vps34 lactylation at Lys356 and Lys781 (via KAT5/TIP60), enhancing Vps34 association with Beclin1, Atg14L, and UVRAG and increasing Vps34 lipid kinase activity, thereby promoting autophagic flux. Co-immunoprecipitation, in vitro kinase assay, mass spectrometry identification of lactylation sites, site-directed mutagenesis, Vps34 lipid kinase activity assay Science advances Medium 37267363
2018 USP20 (ubiquitin-specific protease 20) binds to and stabilizes ULK1 by removing ubiquitin moieties, preventing lysosomal degradation of ULK1 at basal state. Depletion of USP20 inhibits LC3 puncta formation and autophagy initiation. At later stages of autophagy, USP20 dissociates from ULK1, leading to ULK1 degradation. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, autophagy flux assays EMBO reports Medium 29487085
2022 TRIM27 directly polyubiquitinates ULK1 at Lys568 and Lys571 with K48-linked chains for proteasomal degradation, maintaining basal ULK1 levels. During starvation-induced autophagy, TRIM27 also catalyzes K6- and K11-linked ubiquitination of STK38L, activating STK38L which then phosphorylates ULK1 at Ser495, rendering ULK1 susceptible to TRIM27-mediated hyper-ubiquitination to restrain autophagy amplitude. Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis, in vitro kinase assay, mouse knockout models EMBO journal High 35670107
2020 ULK1-ATG13 complex is phosphorylated by CDK1/cyclin B in mitosis. CDK1-induced ULK1-ATG13 phosphorylation promotes mitotic autophagy and cell cycle progression. Double knockout of ULK1 and ATG13 blocks cell cycle progression and decreases cancer cell proliferation. Mass spectrometry, site-directed mutagenesis, co-immunoprecipitation, cell cycle analysis, CRISPR KO, mouse xenograft model PLoS biology Medium 32516310
2020 ULK1 phosphorylates RIPK1 at multiple sites, including Ser357 within its intermediate domain, reducing complex IIb/necrosome assembly and inhibiting TNF-induced apoptosis and necroptosis. Loss of ULK1 enhances TNF-induced cell death. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, cell death assays, ULK1 KO cells Cell reports Medium 32320653
2021 ULK1 directly phosphorylates the regulatory PP2A subunit striatin, activating PP2A. This creates a positive feedback loop where ULK1-activated PP2A promotes autophagy-dependent protein turnover. ULK1 is also itself a PP2A target (dephosphorylated by PP2A). Quantitative phosphoproteomics, in vitro kinase assay, co-immunoprecipitation, PP2A activity assay Cell reports Medium 34592149
2018 ULK1 is the principal kinase responsible for phosphorylation of the mineralocorticoid receptor (MR) at Ser843, as identified by a high-throughput screen of 197 kinases and confirmed by in vitro kinase assay, mass spectrometry, and siRNA knockdown. ULK1/2 double KO mouse embryonic fibroblasts show markedly reduced MRS843 phosphorylation. ULK1 activity is itself inhibited by angiotensin II-induced mTOR-mediated phosphorylation. High-throughput kinase screen, in vitro kinase assay, mass spectrometry, siRNA knockdown, ULK1/2 double KO MEFs Cell reports High 30021155
2024 ULK1 is palmitoylated by the palmitoyltransferase ZDHHC13 upon autophagy induction, and this palmitoylation is required for ULK1 translocation to autophagosome formation sites. Palmitoylated ULK1 enhances phosphorylation of ATG14L, activating PI3-kinase activity and promoting phosphatidylinositol 3-phosphate production needed for autophagosome membrane formation. Acyl-RAC palmitoylation assay, ZDHHC13 knockout/knockdown, live-cell imaging, in vitro kinase assay Nature communications High 39169022
2015 The chaperone-like protein p32 forms a complex with ULK1 and regulates its stability. p32 depletion promotes K48-linked polyubiquitination and proteasomal degradation of ULK1 while impairing K63-linked ubiquitination, resulting in impaired starvation-induced autophagic flux and mitophagy. Restoring ULK1 expression in p32-depleted cells rescues autophagy and mitophagy defects. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, rescue experiments, mitophagy assays Cell death and differentiation Medium 25909887
2019 USP24, encoded by the PD-risk PARK10 locus, regulates ULK1 stability by affecting its ubiquitination. USP24 knockdown elevates ULK1 protein levels and increases autophagy flux in a manner independent of mTORC1 but dependent on class III PI3K activity. siRNA knockdown, co-immunoprecipitation, ubiquitination assay, autophagy flux assays, iPSC-derived dopaminergic neurons Autophagy Medium 30957634
2020 TRAF3 forms a complex with TRAF2 and cIAP1 and mediates K48-linked ubiquitination and degradation of ULK1, promoting mitochondrial ROS production and inflammasome-mediated pyroptosis in macrophages. ULK1 knockdown promotes LPS/nigericin-induced inflammasome activation. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, ROS measurement, inflammasome activation assays FASEB journal Medium 32275117
2024 DRAK2 directly phosphorylates ULK1 at Ser56, inducing ULK1 ubiquitylation and proteasomal degradation, thereby suppressing autophagy and impairing pancreatic β cell function. ULK1-S56A mutation or DRAK2 inhibition preserves mitochondrial function and insulin secretion against lipotoxicity. Phosphoproteomics, in vitro kinase assay, site-directed mutagenesis, conditional knockout mice, autophagy flux assays Science translational medicine High 38324636
2023 ULK1 phosphorylates the SNARE protein YKT6, preventing premature bundling with vacuolar/lysosomal SNAREs (Vam3, Vti1) and inhibiting premature autophagosome-lysosome fusion. This regulation of YKT6 is conserved from yeast to mammals. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, SNARE bundling assay, genetic analysis in yeast and C. elegans Journal of cell science High 36644903
2023 The ULK1 complex effector BAG2 regulates autophagy initiation: in growth conditions, unphosphorylated BAG2 sequesters AMBRA1 away from the ER, attenuating autophagy. Under starvation, ULK1 phosphorylates BAG2 at Ser31, supporting AMBRA1 recruitment to the ER membrane and promoting autophagy initiation. Affinity purification- and proximity labeling-MS interactome, co-immunoprecipitation, in vitro kinase assay, subcellular localization by imaging Cell reports Medium 39207901
2022 ULK1 physically interacts with SARM1 (via SARM1's SAM domains) in vitro and in vivo; this interaction increases upon neurite damage. ULK1 inhibition or knockdown attenuates neurite fragmentation and SARM1 puncta accumulation in neurons, suggesting ULK1-SARM1 interaction contributes to axonal degeneration. Co-immunoprecipitation, domain mutagenesis, ULK1 siRNA knockdown, pharmacological inhibition, spinal cord injury mouse model PNAS Medium 36375051
2023 ULK1 forms large clusters of up to 161 molecules at the ER during amino acid starvation. Clusters with ≥30 molecules are required for autophagosome formation. ULK1 activity is dispensable for initial clustering but required for subsequent cluster expansion involving Atg14, Atg16, and LC3B; expansion also requires Vps34 activity. Quantitative photoactivated localization microscopy (PALM) with single-molecule sensitivity, CRISPR-based endogenous tagging, pharmacological inhibitors Science advances High 37774021
2023 ULK1 phosphorylates SH3PXD2A/TKS5 upon mTOR inactivation by starvation, leading to MMP14 upregulation and promoting cell migration in ovarian carcinoma through a starvation-induced pathway. In vitro kinase assay, site-directed mutagenesis, LC-MS/MS, cell migration assays Autophagy Medium 37505094
2023 ULK1/2 phosphorylates paxillin (PXN) at Ser32 and Ser119, weakening its homotypic interactions and liquid-liquid phase separation, thereby impairing focal adhesion assembly and inhibiting breast cancer cell migration. ULK1/2 and FAK/Src have opposing effects on PXN-dependent mechanotransduction and compete for adjacent serine/tyrosine residues. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, phase separation assay, focal adhesion imaging, cell migration assays EMBO reports High 37846507
2021 In fission yeast, Atg1 kinase activity requires Atg11 (FIP200 ortholog) but not Atg13. A 62-amino-acid region of Atg11 containing an Atg1-binding domain and a homodimerization domain is sufficient for Atg1 activation. Atg11 activates Atg1 by mediating its dimerization, enabling cis-autophosphorylation of Atg1. In vitro kinase assay, domain mutagenesis, artificial dimerization rescue experiments, genetic analysis in S. pombe eLife High 32909946
2019 PP2C phosphatases Ptc2 and Ptc3 in yeast directly dephosphorylate Atg13 and Atg1, promoting macroautophagy induction. These phosphatases interact with the Atg1-Atg13 complex; in their absence, starvation-induced autophagy is inhibited and PAS recruitment of essential autophagy machinery is impaired. Genetic screens, in vitro phosphatase assay, co-immunoprecipitation, GFP-Atg8 flux assays, PAS imaging PNAS Medium 30655342
2014 In S. cerevisiae, the Atg1 complex assembly follows a hierarchical mechanism: Atg1 and Atg13 form a tight complex (~100 nM affinity) via their mutually interacting domains (EAT domain of Atg1 and central domain of Atg13), which then binds as a unit to the Atg17-Atg31-Atg29 scaffold (~10 µM affinity) via Atg13. The resulting complex forms primarily a dimer of pentamers in solution. Hydrogen-deuterium exchange coupled to mass spectrometry, binding affinity measurements, analytical ultracentrifugation PNAS High 25139988
2010 Atg1 activation requires phosphorylation of Thr226 and Ser230 in the activation loop of its kinase domain; mutation of either site abolishes kinase activity and function in autophagy and the Cvt pathway, without affecting Atg1 localization to the PAS or assembly of the Atg1 kinase complex. Quantitative mass spectrometry phosphoproteomics, site-directed mutagenesis, in vitro kinase assay, yeast genetic analysis Autophagy High 20953146
2012 Atg8/LC3 directly binds Atg1/ULK1 via an LIR-dependent interaction, targeting Atg1/ULK1 to autophagosomes. This promotes autophagosome maturation and/or vacuolar fusion. Atg8 binding also triggers vacuolar degradation of the Atg1-Atg13 complex, coupling Atg1 activity to autophagic flux. Separately, Atg13 directly and constitutively binds Atg1 (not regulated by TORC1 in mammals), and mutations abolishing this interaction impair Atg1 function. Co-immunoprecipitation, LIR mutagenesis, in vivo autophagy assays in yeast and mammalian cells, fluorescence microscopy EMBO journal High 22885598
2023 Hsp90 forms a complex with Atg1/ULK1, suppressing its kinase activity. Upon autophagy-inducing stimuli, Atg1/ULK1 phosphorylates a conserved serine in the Hsp90 amino domain, inhibiting Hsp90 ATPase activity and altering chaperone dynamics, leading to dissociation of the Hsp90:Atg1/ULK1 complex and activation of Atg1/ULK1. Co-immunoprecipitation, in vitro kinase assay, ATPase activity assay, mutagenesis, NMR/HDX analysis of Hsp90 conformational dynamics Cell reports Medium 37453059
2020 In S. cerevisiae, Atg1 phosphorylates Ykt6 SNARE, keeping it in an inactive state by preventing its interaction with vacuolar SNAREs Vam3 and Vti1, thereby preventing premature autophagosome-vacuole fusion. In vitro kinase assay, co-immunoprecipitation, SNARE bundling assay, yeast genetic analysis EMBO reports High 33274589
2014 In S. cerevisiae, Atg1 phosphorylates Atg9 and this phosphorylation is required for phagophore elongation. The Atg1 consensus phosphorylation sequence was determined using a peptide array approach. Peptide array-based phosphorylation consensus determination, in vitro kinase assay, yeast genetic analysis Autophagy Medium 24905091
2021 In S. cerevisiae, Atg1 phosphorylates Atg13, triggering Atg1 complex dissociation and enabling rapid turnover of Atg1 complex subunits at the PAS. Atg1 is activated by lipidated Atg8 (Atg8-PE), stimulating substrate phosphorylation along the growing autophagosomal membrane. Atg1 also self-regulates Atg8-PE levels by phosphorylating and inhibiting the Atg8-specific E2 and E3 enzymes. In vitro reconstitution with lipidated Atg8, in vitro kinase assays, mutagenesis, live imaging of PAS dynamics Molecular cell High 34798055
2022 In S. cerevisiae, Atg1 phosphorylates Atg11 at Ser949, Ser1057, and Ser1064 in its CC4 domain; phosphorylation of these sites is required for Atg11 binding to selective autophagy receptors and for efficient cytoplasm-to-vacuole targeting, mitophagy, reticulophagy, and pexophagy. In vitro kinase assay, mass spectrometry, site-directed mutagenesis, selective autophagy substrate cleavage assays Autophagy High 35427192
2023 The PI3KCI complex in S. cerevisiae is recruited to the pre-autophagosomal structure via interaction of its Atg38 subunit with the Atg1 complex; this interaction is enhanced upon macroautophagy induction in an Atg1 kinase activity-dependent manner. Co-immunoprecipitation, domain mutagenesis, yeast genetic analysis, fluorescence microscopy Journal of Cell Biology Medium 37436710
2020 Drosophila Atg1/ULK1 directly phosphorylates the transcriptional co-activator Yorkie at Ser74 and Ser97 (confirmed by in vitro kinase assay), preventing its binding to Scalloped and inhibiting Yorkie's growth-promoting activity. This regulation is independent of Atg13 and the Hippo-Warts pathway, representing a non-autophagy function of Atg1. In vitro kinase assay, Drosophila genetics (gain-of-function and loss-of-function), co-immunoprecipitation Developmental cell Medium 32032548
2007 In Drosophila, overexpression of Atg1 is sufficient to induce autophagy and this requires its kinase activity. Atg1-induced autophagy leads to caspase-dependent apoptotic cell death. Atg1 expression inhibits cell growth and causes negative feedback on TOR activity. Drosophila genetics, overexpression and loss-of-function studies, kinase-dead mutagenesis, caspase activity assays, TOR reporter assays Current biology Medium 17208179
2007 In Drosophila, ATG1 inhibits TOR/S6K-dependent cell growth by blocking S6K phosphorylation at Thr389. ATG1 knockdown in mammalian cells induces ectopic S6K activation and S6 phosphorylation. This demonstrates cross-talk between autophagy and cell growth regulation through ATG1-mediated S6K inhibition. Drosophila genetics, siRNA knockdown in mammalian cells, in vitro kinase assay, immunoblotting for pS6K EMBO reports Medium 17347671

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature cell biology 5964 21258367
2010 Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science (New York, N.Y.) 2177 21205641
2013 ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nature cell biology 1303 23685627
2006 Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. Journal of cell science 655 16940348
2017 The mammalian ULK1 complex and autophagy initiation. Essays in biochemistry 653 29233870
2007 Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Current biology : CB 590 17208179
2014 ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO reports 479 24671035
2013 The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 404 23295650
2019 Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy. Molecular cell 394 30853401
2013 Autophagosome formation--the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage. Seminars in cancer biology 234 23727157
2012 Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy. The EMBO journal 222 22885598
2023 ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Science advances 202 37267363
2020 SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity. Autophagy 191 31913745
2020 p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease. The Journal of clinical investigation 180 32804155
2020 MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis. Autophagy 177 33213267
2021 Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis. Cells 171 35011593
2019 ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97. Molecular cell 154 30979586
2011 ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 147 21795849
2016 Regulation of Autophagy By Signaling Through the Atg1/ULK1 Complex. Journal of molecular biology 145 27059781
2007 ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase. EMBO reports 132 17347671
2016 Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation. The Journal of cell biology 124 27932573
2009 Evolution of Atg1 function and regulation. Autophagy 108 19411825
2015 Atg1 family kinases in autophagy initiation. Cellular and molecular life sciences : CMLS 106 25948417
2013 The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis. Biochemical Society transactions 105 23863160
2021 ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3. Scientific reports 90 34654847
2019 Recruitment and Activation of the ULK1/Atg1 Kinase Complex in Selective Autophagy. Journal of molecular biology 90 31351898
2020 NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter. Cell death & disease 86 31959741
2019 GABARAPs and LC3s have opposite roles in regulating ULK1 for autophagy induction. Autophagy 86 31208283
2022 NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway. Communications biology 82 36068299
2022 Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications. Acta pharmaceutica Sinica. B 81 36213540
2011 Regulation of the autophagy initiating kinase ULK1 by nutrients: roles of mTORC1 and AMPK. Cell cycle (Georgetown, Tex.) 78 21403467
2019 Multilayered Control of Protein Turnover by TORC1 and Atg1. Cell reports 76 31553916
2018 The ULK1-FBXW5-SEC23B nexus controls autophagy. eLife 71 30596474
2014 Assembly and dynamics of the autophagy-initiating Atg1 complex. Proceedings of the National Academy of Sciences of the United States of America 67 25139988
2020 A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer. Cancers 65 32033142
2020 The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death. Cell reports 63 32320653
2022 Oxygen-sensitive methylation of ULK1 is required for hypoxia-induced autophagy. Nature communications 61 35246531
2019 PP2C phosphatases promote autophagy by dephosphorylation of the Atg1 complex. Proceedings of the National Academy of Sciences of the United States of America 60 30655342
2017 Canonical and noncanonical functions of ULK/Atg1. Current opinion in cell biology 58 28292700
2022 TRIM27 cooperates with STK38L to inhibit ULK1-mediated autophagy and promote tumorigenesis. The EMBO journal 56 35670107
2021 GSK3B induces autophagy by phosphorylating ULK1. Experimental & molecular medicine 56 33654220
2020 Fine-tuning of AMPK-ULK1-mTORC1 regulatory triangle is crucial for autophagy oscillation. Scientific reports 56 33082544
2010 Activation of Atg1 kinase in autophagy by regulated phosphorylation. Autophagy 55 20953146
2019 The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia. Science translational medicine 52 31434755
2018 The deubiquitinating enzyme USP20 stabilizes ULK1 and promotes autophagy initiation. EMBO reports 49 29487085
2020 ULK1-ATG13 and their mitotic phospho-regulation by CDK1 connect autophagy to cell cycle. PLoS biology 48 32516310
2006 Function of the Dictyostelium discoideum Atg1 kinase during autophagy and development. Eukaryotic cell 48 17031001
2020 ULK1 phosphorylates Exo70 to suppress breast cancer metastasis. Nature communications 47 31913283
2017 ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic. BMC cell biology 45 28486929
2015 Chaperone-like protein p32 regulates ULK1 stability and autophagy. Cell death and differentiation 45 25909887
2020 Mir214-3p and Hnf4a/Hnf4α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis. Autophagy 44 33078654
2019 The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability. Autophagy 43 30957634
2024 Physiological functions of ULK1/2. Journal of molecular biology 41 38311233
2014 Atg1 kinase organizes autophagosome formation by phosphorylating Atg9. Autophagy 41 24905091
2020 TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 32275117
2018 The NF-κB Factor Relish Regulates Atg1 Expression and Controls Autophagy. Cell reports 39 30463009
2016 Regulation of ULK1 Expression and Autophagy by STAT1. The Journal of biological chemistry 37 28011640
2013 ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression. Protein & cell 37 27023913
2020 Atg1 kinase regulates autophagosome-vacuole fusion by controlling SNARE bundling. EMBO reports 36 33274589
2021 ULK1 phosphorylation of striatin activates protein phosphatase 2A and autophagy. Cell reports 35 34592149
2011 ULK1, mammalian target of rapamycin, and mitochondria: linking nutrient availability and autophagy. Antioxidants & redox signaling 35 21235397
2018 ULK1 Phosphorylates and Regulates Mineralocorticoid Receptor. Cell reports 33 30021155
2024 Palmitoylation of ULK1 by ZDHHC13 plays a crucial role in autophagy. Nature communications 32 39169022
2022 Icariin alleviates osteoarthritis through PI3K/Akt/mTOR/ULK1 signaling pathway. European journal of medical research 32 36253872
2011 Atg1 allows second-signaled autophagic cell death in Dictyostelium. Autophagy 31 21301205
2023 Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery. Cell reports 30 37453059
2023 The Atg1 complex, Atg9, and Vac8 recruit PI3K complex I to the pre-autophagosomal structure. The Journal of cell biology 28 37436710
2022 Function and regulation of ULK1: From physiology to pathology. Gene 28 35905845
2021 Multilayered regulation of autophagy by the Atg1 kinase orchestrates spatial and temporal control of autophagosome formation. Molecular cell 28 34798055
2020 Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation. eLife 27 32909946
2023 An ULK1/2-PXN mechanotransduction pathway suppresses breast cancer cell migration. EMBO reports 25 37846507
2016 Atg1-independent induction of autophagy by the Drosophila Ulk3 homolog, ADUK. The FEBS journal 25 27717182
2024 DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition. Science translational medicine 24 38324636
2024 Regulation of ULK1 by WTAP/IGF2BP3 axis enhances mitophagy and progression in epithelial ovarian cancer. Cell death & disease 23 38286802
2022 Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function. Autophagy 23 35104184
2019 Ulk1/Rab9-mediated alternative mitophagy confers cardioprotection during energy stress. The Journal of clinical investigation 23 30667375
2023 Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy. Frontiers in endocrinology 22 36743936
2022 TRK-fused gene (TFG) regulates ULK1 stability via TRAF3-mediated ubiquitination and protects macrophages from LPS-induced pyroptosis. Cell death & disease 21 35091545
2022 ULK1 Signaling in the Liver: Autophagy Dependent and Independent Actions. Frontiers in cell and developmental biology 21 35252196
2024 ULK/Atg1: phasing in and out of autophagy. Trends in biochemical sciences 20 38565496
2021 TFG binds LC3C to regulate ULK1 localization and autophagosome formation. The EMBO journal 20 33932238
2016 Beyond autophagy: New roles for ULK1 in immune signaling and interferon responses. Cytokine & growth factor reviews 20 27068414
2007 Contribution of Atg1-dependent autophagy to TOR-mediated cell growth and survival. Autophagy 20 17525525
2023 ULK1-mediated phosphorylation regulates the conserved role of YKT6 in autophagy. Journal of cell science 19 36644903
2022 Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury. Proceedings of the National Academy of Sciences of the United States of America 19 36375051
2023 Starvation-inactivated MTOR triggers cell migration via a ULK1-SH3PXD2A/TKS5-MMP14 pathway in ovarian carcinoma. Autophagy 18 37505094
2023 ULK1 forms distinct oligomeric states and nanoscopic structures during autophagy initiation. Science advances 18 37774021
2020 Yorkie Growth-Promoting Activity Is Limited by Atg1-Mediated Phosphorylation. Developmental cell 18 32032548
2023 Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors. Molecular cancer research : MCR 17 36573964
2022 TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy. Cell death & disease 17 35393404
2022 Sestrin 2 Deficiency Exacerbates Noise-Induced Cochlear Injury Through Inhibiting ULK1/Parkin-Mediated Mitophagy. Antioxidants & redox signaling 17 35708118
2022 STAT3 suppresses the AMPKα/ULK1-dependent induction of autophagy in glioblastoma cells. Journal of cellular and molecular medicine 16 35670018
2024 Deubiquitinase USP10 promotes osteosarcoma autophagy and progression through regulating GSK3β-ULK1 axis. Cell & bioscience 15 39218913
2024 α-Synuclein disrupts microglial autophagy through STAT1-dependent suppression of Ulk1 transcription. Journal of neuroinflammation 15 39462396
2022 Atg1-mediated Atg11 phosphorylation is required for selective autophagy by regulating its association with receptor proteins. Autophagy 15 35427192
2024 The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization. Cell reports 14 39207901
2023 Cyclin-G-associated kinase GAK/dAux regulates autophagy initiation via ULK1/Atg1 in glia. Proceedings of the National Academy of Sciences of the United States of America 14 37428930
2023 The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy. Cell death & disease 14 37607937
2021 Vacuolar protein Tag1 and Atg1-Atg13 regulate autophagy termination during persistent starvation in S. cerevisiae. Journal of cell science 14 33536246
2024 IL-33 Accelerates Chronic Atrophic Gastritis through AMPK-ULK1 Axis Mediated Autolysosomal Degradation of GKN1. International journal of biological sciences 13 38617533

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