{"gene":"ULK2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1999,"finding":"ULK2 is a serine/threonine kinase that undergoes autophosphorylation in vitro; truncation mutants mapped autophosphorylation to the proline/serine-rich (PS) domain. ULK2 shares domain architecture (N-terminal kinase domain, central PS domain, C-terminal domain) with ULK1 and C. elegans UNC-51. Chimeric ULK2/UNC-51 constructs showed kinase and PS domain functions are conserved across species while the C domain acts in a species-specific manner.","method":"In vitro kinase autophosphorylation assay with truncation mutants; ULK2/UNC-51 chimeric constructs expressed in COS7 cells; C. elegans rescue assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay with mutagenesis/truncation, single lab, no replication","pmids":["10557072"],"is_preprint":false},{"year":2011,"finding":"ULK1 and ULK2 are functionally redundant serine/threonine kinases required for autophagy induction under amino acid deprivation in MEFs; double knockout of ULK1 and ULK2 blocks amino acid starvation-induced autophagy but not glucose-deprivation-induced autophagy. Ammonia-induced autophagy proceeds independently of ULK1/ULK2.","method":"Genetic double knockout (Ulk1/2-/- MEFs); autophagy readouts (LC3 conversion, electron microscopy)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic double KO with multiple autophagy readouts, replicated by independent labs","pmids":["21690395"],"is_preprint":false},{"year":2011,"finding":"ULK1 and ULK2 are functionally redundant in mediating starvation-induced autophagy in fibroblasts, but ULK1 (not ULK2) is specifically required for autophagy in cerebellar granule neurons responding to low potassium, demonstrating cell-type-specific non-redundancy.","method":"Single and double knockout MEFs and cerebellar granule neurons; autophagy assays (LC3-II levels, autophagosome formation)","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in two distinct cell types with specific phenotypic readouts, consistent with other KO studies","pmids":["21460635"],"is_preprint":false},{"year":2011,"finding":"Atg13-dependent autophagy induction can proceed independently of ULK1 and ULK2; simultaneous Ulk1/Ulk2 double knockout did not phenocopy Atg13 deficiency, and ULK1-dependent phosphorylation sites in Atg13 were found dispensable for autophagy induction.","method":"Ulk1/2 double knockout cells; Atg13-deficient cells; phosphorylation site mutagenesis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double KO and mutagenesis, single lab","pmids":["22024743"],"is_preprint":false},{"year":2011,"finding":"Ulk2 promotes neuropil elaboration in zebrafish habenular neurons, and this activity is asymmetrically inhibited by Kctd12.1, which physically interacts with Ulk2. Knockdown of Ulk2 reduces asymmetric neuropil elaboration; overexpression causes excess neuropil. This interaction was identified through a screen for Kctd12.1-interacting proteins.","method":"Protein interaction screen; zebrafish knockdown and overexpression; morphological analysis of habenular neuropil","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction screen plus functional gain/loss-of-function in zebrafish, single lab","pmids":["21734278"],"is_preprint":false},{"year":2013,"finding":"ULK2 knockdown in differentiated 3T3-L1 adipocytes reduces basal and mTORC1 inhibition-induced autophagy, reduces basal lipolysis, reduces mitochondrial respiration, and has opposing effects to ULK1 knockdown on fatty acid oxidation and fatty acid uptake, indicating functionally distinct roles for ULK1 and ULK2 in lipid metabolism.","method":"shRNA knockdown of Ulk1 and Ulk2 in differentiated 3T3-L1 adipocytes; lipolysis assays; Seahorse metabolic flux analysis; autophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with multiple metabolic readouts, single lab, two orthogonal functional assays","pmids":["24135897"],"is_preprint":false},{"year":2014,"finding":"ULK2 overexpression induces autophagy and inhibits growth of glioma cells; this growth inhibition requires kinase activity (kinase-dead mutant fails to induce autophagy or inhibit growth) and is autophagy-dependent (abolished in ATG5-/- cells). ULK2 also inhibits anchorage-independent growth and astrocyte transformation in vitro and tumor growth in vivo.","method":"Ectopic overexpression of wild-type and kinase-dead ULK2; ATG5+/+ and ATG5-/- iBMK cells; autophagy assays; anchorage-independent growth assay; in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active-site mutagenesis with genetic epistasis using ATG5 KO, single lab","pmids":["24923441"],"is_preprint":false},{"year":2015,"finding":"ULK2 is transported into the nucleus via karyopherin beta 2 (Kapβ2) through a PY-NLS motif (residues 774-795) in its S/P spacer domain. PKA phosphorylation of ULK2 at Ser1027 promotes nuclear localization, functional dissociation from Atg13 and FIP200, and reduced autophagic activity. Mutation of the Kapβ2-binding motif (P794A) retained ULK2 in the cytoplasm and increased autophagy activity.","method":"In vitro and in vivo pull-down of ULK2 with Kapβ2; confocal co-localization; site-directed mutagenesis (P794A, Ser1027); autophagy activity assay; in vitro kinase assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down, mutagenesis, and localization with functional consequence, single lab","pmids":["26052940"],"is_preprint":false},{"year":2017,"finding":"ULK2 binds to and phosphorylates CARMA2sh in human keratinocytes, thereby inhibiting CARMA2sh-mediated NF-κB activation by promoting lysosomal degradation of BCL10. Psoriasis-associated missense mutations in CARMA2sh escape ULK2-mediated phosphorylation and inhibition.","method":"Co-immunoprecipitation; in vitro kinase assay; NF-κB reporter assay; lysosomal degradation assay; psoriasis mutant analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vitro kinase assay plus functional NF-κB readout, single lab","pmids":["28230860"],"is_preprint":false},{"year":2017,"finding":"ULK1 and ULK2 are required for proper axon guidance and defasciculation in the developing mouse forebrain (corpus callosum, anterior commissure, corticothalamic and thalamocortical axons) via an autophagy-independent pathway, as these defects were not recapitulated by loss of Atg7 or Rb1cc1.","method":"CNS-specific conditional Ulk1/2 double knockout mice (Nes-Cre); Atg7 and Rb1cc1 knockout comparison; brain histology; axon tracing","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional double KO with genetic epistasis using multiple autophagy gene KOs, multiple orthogonal anatomical readouts","pmids":["29099309"],"is_preprint":false},{"year":2018,"finding":"Ulk2 heterozygous loss in mice leads to p62 upregulation in prefrontal cortex pyramidal neurons, reduced GABAA receptor surface expression, and excitatory-inhibitory imbalance. Reducing p62 genetically or pharmacologically, or blocking p62-GABARAPL2 interaction with a peptide, restores GABAA receptor surface expression and rescues behavioral deficits, placing ULK2 upstream of p62-mediated regulation of GABAA receptor endocytic trafficking.","method":"Ulk2+/- mice; immunofluorescence; electrophysiology; receptor surface expression assay; genetic p62 reduction; peptide interference; behavioral tests","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic, pharmacological, peptide interference) with rescue of cellular and behavioral phenotypes, single lab","pmids":["29893844"],"is_preprint":false},{"year":2019,"finding":"ULK1 and ULK2 localize to stress granules, phosphorylate VCP/p97, and thereby increase VCP's ATPase activity and ability to disassemble stress granules. Loss of ULK1/2 in mice causes vacuolar myopathy with ubiquitin- and TDP-43-positive inclusions similar to VCP mutation-associated inclusion body myopathy.","method":"Ulk1/2 double knockout mouse model; co-localization of ULK1/2 with stress granule markers; in vitro phosphorylation of VCP; VCP ATPase activity assay; stress granule disassembly assay; ULK1/2 agonist treatment","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay on VCP substrate plus functional stress granule disassembly readout plus in vivo KO phenotype, multiple orthogonal methods","pmids":["30979586"],"is_preprint":false},{"year":2019,"finding":"ULK2 (but not ULK1) is specifically required in skeletal muscle for basal selective degradation of insoluble ubiquitinated protein aggregates associated with p62 and NBR1. ULK2 deficiency causes accumulation of these aggregates, myofiber atrophy, and degeneration without impairing autophagy initiation, autophagosome-lysosome fusion, or proteasome/lysosome protease activities.","method":"Muscle-specific ULK2 and ULK1 knockout mice; ubiquitinated protein aggregate fractionation; p62/NBR1 immunostaining; muscle force measurements; lysosome and proteasome activity assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — paralog-specific KO with multiple orthogonal biochemical and functional readouts distinguishing ULK2 from ULK1","pmids":["31361156"],"is_preprint":false},{"year":2021,"finding":"PKCλ/ι directly phosphorylates ULK2, repressing its activity and promoting its degradation via an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι increases enzymatically active ULK2, which then directly phosphorylates and activates TBK1 to stimulate STING-mediated interferon signaling.","method":"In vitro kinase assay (PKCλ/ι phosphorylates ULK2); in vitro kinase assay (ULK2 phosphorylates TBK1); PKCλ/ι knockout and pharmacological inhibition; ULK2 degradation assay; STING pathway reporter; CD8+ T cell recruitment in tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assays for both upstream (PKCλ/ι→ULK2) and downstream (ULK2→TBK1) steps with in vivo functional validation","pmids":["34560002"],"is_preprint":false},{"year":2022,"finding":"Perinatal loss of ULK2 in cardiomyocytes (cU2-KO) enhances basal autophagy dependent on the remaining ULK1, preserving cardiac function. Perinatal double loss of ULK1 and ULK2 impairs autophagy causing age-related cardiomyopathy. Adult-specific loss of ULK2 (icU2-KO) does not cause cardiomyopathy, distinguishing its developmental role from that of ULK1.","method":"Cardiomyocyte-specific and inducible ULK1 and ULK2 knockout mice; autophagy flux assays; cardiac function (echocardiography); mitochondrial respiration; survival analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models (single, double, inducible) with orthogonal cardiac and autophagy readouts","pmids":["35104184"],"is_preprint":false},{"year":2024,"finding":"ULK1 and ULK2 phosphorylate the focal adhesion protein paxillin (PXN) at serine residues, inhibiting focal adhesion assembly and F-actin organization to suppress breast cancer cell migration in an autophagy-independent manner. ULK1/2-mediated serine phosphorylation of PXN counteracts tyrosine phosphorylation by PTK2 and SRC.","method":"ULK1/2 kinase assay on PXN; phosphorylation site mapping; focal adhesion and F-actin imaging; migration assays; autophagy-deficient control conditions","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay on identified substrate with functional migration readout, single lab","pmids":["38163960"],"is_preprint":false},{"year":2014,"finding":"Ulk2 interacts with Kctd12 proteins via its proline/serine-rich domain, and this interaction negatively regulates Ulk2-driven dendrite branching and elaboration in zebrafish habenular neurons. Loss of Kctd12 results in excess branching; loss of Ulk2 reduces dendrite elaboration and increases anxiety-like behavior.","method":"Protein interaction mapping (Kctd12-Ulk2 domain interaction); zebrafish loss-of-function (morpholino/mutant); dendritic morphology quantification; behavioral assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped interaction with reciprocal loss-of-function phenotypes, single lab","pmids":["25329151"],"is_preprint":false},{"year":2025,"finding":"ULK2 forms a stable complex with FIP200, which in turn specifically interacts with AMPK α1 and γ1 subunits (but not other AMPK subunits). shRNA-mediated knockdown of ULK2 activates AMPK and promotes cytoplasmic accumulation of ULK1 and FIP200, thereby inducing autophagy-dependent degradation of BCR::ABL and CML cell death.","method":"Mass spectrometry analysis of ULK2 complex in 293FT cells; shRNA knockdown of ULK2 in CML cells; AMPK activation assay; ULK1/FIP200 localization; BCR::ABL degradation assay; cell viability","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry complex identification plus shRNA KD with multiple functional readouts, single lab","pmids":["40664084"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated m6A modification of ULK2 mRNA upregulates ULK2 expression in hypertrophic scar fibroblasts, enhancing autophagy and driving fibroblast-to-myofibroblast differentiation. Silencing METTL3 impaired autophagic flux and inhibited this differentiation.","method":"MeRIP-seq to identify m6A sites on ULK2 mRNA; METTL3 siRNA knockdown; Western blotting; transmission electron microscopy; LC3-II/I ratio; in vivo siRNA injection in rabbit ear HS model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus KD with multiple orthogonal readouts including in vivo model, single lab","pmids":["40409645"],"is_preprint":false},{"year":2026,"finding":"ULK2 overexpression in cisplatin-resistant ovarian cancer organoids phosphorylates c-Jun at Ser243, promoting c-Jun degradation and suppressing glycolysis, thereby reducing cisplatin resistance. c-Jun overexpression counteracts both the chemosensitivity and glycolytic suppression induced by ULK2.","method":"Phosphoproteomics after ULK2 overexpression in organoids; c-Jun phosphorylation validation; glycolysis assays; CCK-8 and in vivo experiments; c-Jun overexpression rescue","journal":"Science progress","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — phosphoproteomics-identified substrate (c-Jun Ser243) with rescue experiment and functional glycolysis/chemosensitivity readouts, single lab","pmids":["41719166"],"is_preprint":false}],"current_model":"ULK2 is a serine/threonine kinase that autophosphorylates in its PS domain and functions as a mammalian ATG1/UNC-51 ortholog: it forms a complex with FIP200 and Atg13 to initiate autophagy under nutrient stress (redundantly with ULK1 in most cell types, but with tissue-specific unique roles in skeletal muscle and the adult heart); it is negatively regulated by PKCλ/ι phosphorylation (promoting its microautophagic degradation) and by PKA-dependent Ser1027 phosphorylation (driving nuclear import via Kapβ2/PY-NLS and dissociation from Atg13/FIP200); when active, ULK2 phosphorylates downstream substrates including VCP/p97 (promoting stress granule disassembly), TBK1 (activating STING-mediated interferon signaling), paxillin/PXN (inhibiting focal adhesion assembly and cell migration), CARMA2sh (suppressing NF-κB via BCL10 lysosomal degradation), and c-Jun (Ser243, suppressing glycolysis); ULK2 also regulates GABAA receptor surface expression in cortical pyramidal neurons through autophagic control of p62, and promotes neuropil/dendrite elaboration in habenular neurons through interaction with Kctd12."},"narrative":{"mechanistic_narrative":"ULK2 is a serine/threonine kinase that initiates and directs autophagy as the mammalian counterpart of ATG1/UNC-51, sharing an N-terminal kinase domain, central proline/serine-rich (PS) domain, and C-terminal domain with ULK1, and undergoing autophosphorylation within the PS domain [PMID:10557072]. Together with its paralog ULK1, ULK2 is required for amino-acid-starvation-induced autophagy and the two kinases are largely functionally redundant in fibroblasts, yet they diverge in a cell-type-specific manner, with ULK2 carrying unique roles in skeletal muscle, the developing heart, and lipid metabolism [PMID:21690395, PMID:21460635, PMID:31361156, PMID:35104184]. Beyond canonical autophagy initiation, ULK2 acts through autophagy-independent kinase functions on a growing set of substrates: it phosphorylates VCP/p97 to drive stress-granule disassembly [PMID:30979586], activates TBK1 to stimulate STING-mediated interferon signaling [PMID:34560002], phosphorylates paxillin/PXN to oppose focal adhesion assembly and suppress cell migration [PMID:38163960], phosphorylates CARMA2sh to restrain NF-κB activation via lysosomal degradation of BCL10 [PMID:28230860], and phosphorylates c-Jun at Ser243 to suppress glycolysis [PMID:41719166]. ULK2 activity is negatively controlled by PKCλ/ι, which phosphorylates it to promote endosomal microautophagy-driven degradation [PMID:34560002], and by PKA-dependent Ser1027 phosphorylation, which drives Kapβ2/PY-NLS-mediated nuclear import and dissociation from Atg13 and FIP200 [PMID:26052940]. In the nervous system, ULK2 governs habenular neuropil and dendrite elaboration through interaction with Kctd12 [PMID:21734278, PMID:25329151], and regulates GABAA receptor surface expression in cortical pyramidal neurons upstream of p62 [PMID:29893844]. Functionally, ULK2 acts as a growth suppressor in glioma and modulates chemoresistance, consistent with a broad tumor-suppressive role [PMID:24923441, PMID:41719166].","teleology":[{"year":1999,"claim":"Established ULK2 as an autophosphorylating serine/threonine kinase with a conserved ATG1/UNC-51-type domain architecture, defining the structural basis for its catalytic activity.","evidence":"In vitro kinase autophosphorylation assays with truncation mutants and ULK2/UNC-51 chimeras in COS7 cells plus C. elegans rescue","pmids":["10557072"],"confidence":"Medium","gaps":["No physiological substrate identified at this stage","Cellular function not addressed","Single lab, no replication"]},{"year":2011,"claim":"Defined ULK1/ULK2 redundancy in starvation-induced autophagy while revealing both stimulus-specificity and cell-type-specific non-redundancy, refining when ULK2 is functionally required.","evidence":"Single and double Ulk1/2 knockout MEFs and cerebellar granule neurons with LC3/EM autophagy readouts","pmids":["21690395","21460635","22024743"],"confidence":"High","gaps":["Does not resolve molecular basis of ULK2-specific versus ULK1-specific roles","Atg13-independent autophagy mechanism unexplained","Glucose- and ammonia-induced autophagy pathways unmapped"]},{"year":2011,"claim":"Identified ULK2 as a regulator of habenular neuropil elaboration, linking the kinase to neuronal morphogenesis through a Kctd12 interaction.","evidence":"Kctd12.1 interaction screen with zebrafish knockdown/overexpression and habenular morphology analysis","pmids":["21734278"],"confidence":"Medium","gaps":["Kinase substrates in this pathway unidentified","Mechanism of Kctd12-mediated inhibition unknown","Autophagy-dependence not tested"]},{"year":2013,"claim":"Distinguished ULK2 from ULK1 in adipocyte lipid metabolism, showing the paralogs can exert opposing metabolic effects.","evidence":"shRNA knockdown in 3T3-L1 adipocytes with lipolysis, Seahorse flux, and autophagy assays","pmids":["24135897"],"confidence":"Medium","gaps":["Substrates underlying metabolic effects unknown","Knockdown rather than clean genetic deletion","Mechanism of opposing ULK1/ULK2 effects unresolved"]},{"year":2014,"claim":"Established ULK2 as a kinase-dependent, autophagy-dependent growth suppressor in glioma, connecting its catalytic activity to tumor suppression.","evidence":"Wild-type versus kinase-dead overexpression in ATG5+/+ and ATG5-/- cells with growth and xenograft assays","pmids":["24923441"],"confidence":"Medium","gaps":["Overexpression-based, endogenous role untested","Relevant substrates not identified","Single lab"]},{"year":2014,"claim":"Mapped the Kctd12-ULK2 interaction to the PS domain and tied it to dendrite elaboration and anxiety-like behavior, deepening the neuronal morphogenesis role.","evidence":"Domain-mapped interaction with zebrafish loss-of-function and dendrite/behavioral quantification","pmids":["25329151"],"confidence":"Medium","gaps":["Kinase activity requirement not established","Downstream effectors unknown","Single lab"]},{"year":2015,"claim":"Revealed PKA-driven, Kapβ2/PY-NLS-mediated nuclear import as a switch that dissociates ULK2 from Atg13/FIP200 and dampens autophagy, providing a regulatory off-switch.","evidence":"Reciprocal Kapβ2 pull-down, confocal co-localization, P794A/Ser1027 mutagenesis, and autophagy assays","pmids":["26052940"],"confidence":"Medium","gaps":["Nuclear function of ULK2 undefined","PKA upstream signal context unmapped","Single lab"]},{"year":2017,"claim":"Identified CARMA2sh as a ULK2 substrate, linking the kinase to NF-κB suppression and psoriasis-associated signaling.","evidence":"Co-IP, in vitro kinase assay, NF-κB reporter, lysosomal degradation assay, and psoriasis mutant analysis","pmids":["28230860"],"confidence":"Medium","gaps":["Phosphosite on CARMA2sh not pinpointed in narrative","In vivo relevance untested","Single lab"]},{"year":2017,"claim":"Demonstrated an autophagy-independent requirement for ULK1/ULK2 in forebrain axon guidance, establishing non-autophagic functions in CNS development.","evidence":"Nes-Cre conditional Ulk1/2 double knockout mice with Atg7/Rb1cc1 epistasis and axon tracing","pmids":["29099309"],"confidence":"High","gaps":["Substrates mediating axon guidance unknown","ULK2-specific contribution not separated from ULK1","Mechanism of guidance unresolved"]},{"year":2018,"claim":"Placed ULK2 upstream of p62-mediated GABAA receptor trafficking, linking its loss to excitatory-inhibitory imbalance and behavioral deficits.","evidence":"Ulk2+/- mice with electrophysiology, receptor surface assays, genetic/pharmacological/peptide p62 rescue, and behavior","pmids":["29893844"],"confidence":"High","gaps":["Direct ULK2 substrate in this pathway unidentified","Connection to canonical autophagy machinery not fully defined","Single lab"]},{"year":2019,"claim":"Identified VCP/p97 as a ULK1/ULK2 substrate driving stress granule disassembly, and skeletal-muscle ULK2 as required for selective clearance of ubiquitinated aggregates, defining proteostatic functions.","evidence":"Ulk1/2 double KO and muscle-specific paralog-specific KO mice with in vitro VCP phosphorylation, ATPase/disassembly assays, and aggregate fractionation","pmids":["30979586","31361156"],"confidence":"High","gaps":["VCP phosphosite mapping limited","How ULK2 selectively recognizes aggregates unknown","Relationship to autophagosome formation in muscle not fully resolved"]},{"year":2021,"claim":"Defined a complete upstream-downstream signaling axis: PKCλ/ι represses and degrades ULK2 via endosomal microautophagy, while active ULK2 phosphorylates TBK1 to drive STING interferon signaling and antitumor immunity.","evidence":"In vitro kinase assays for both PKCλ/ι→ULK2 and ULK2→TBK1 steps with PKCλ/ι KO/inhibition, STING reporter, and CD8+ T cell tumor models","pmids":["34560002"],"confidence":"High","gaps":["TBK1 phosphosite not detailed","Balance between ULK2 autophagic and immune functions unclear","Single lab"]},{"year":2022,"claim":"Separated developmental from adult cardiac roles, showing perinatal but not adult ULK2 loss is compensated by ULK1, clarifying tissue- and timing-specific essentiality.","evidence":"Cardiomyocyte-specific, double, and inducible KO mice with autophagy flux, echocardiography, and mitochondrial respiration","pmids":["35104184"],"confidence":"High","gaps":["Molecular basis of developmental versus adult difference unknown","ULK2-unique substrates in heart unidentified"]},{"year":2024,"claim":"Identified paxillin as a ULK1/ULK2 substrate whose serine phosphorylation opposes focal adhesion assembly and PTK2/SRC tyrosine signaling, defining an autophagy-independent role in migration.","evidence":"In vitro kinase assay on PXN, phosphosite mapping, focal adhesion/F-actin imaging, and migration assays with autophagy-deficient controls","pmids":["38163960"],"confidence":"Medium","gaps":["In vivo relevance for metastasis untested","ULK2-specific versus ULK1 contribution not separated","Single lab"]},{"year":2025,"claim":"Resolved a stable ULK2-FIP200 complex that links to AMPK α1/γ1 subunits and showed ULK2 loss activates AMPK to promote autophagic BCR::ABL degradation, extending ULK2 regulation to leukemia.","evidence":"Mass spectrometry of the ULK2 complex in 293FT cells with shRNA knockdown, AMPK activation, localization, and BCR::ABL degradation assays in CML cells","pmids":["40664084"],"confidence":"Medium","gaps":["Direction of AMPK-ULK2 regulation incompletely defined","Knockdown rather than genetic deletion","Single lab"]},{"year":2025,"claim":"Showed METTL3-mediated m6A modification upregulates ULK2 to enhance autophagy and drive fibroblast-to-myofibroblast differentiation, identifying an upstream transcript-level control of ULK2.","evidence":"MeRIP-seq, METTL3 siRNA knockdown, autophagy readouts, and in vivo rabbit ear hypertrophic scar model","pmids":["40409645"],"confidence":"Medium","gaps":["m6A reader mediating ULK2 upregulation unidentified","Direct kinase substrates in fibrosis unknown","Single lab"]},{"year":2026,"claim":"Identified c-Jun Ser243 as a ULK2 substrate whose phosphorylation promotes c-Jun degradation, suppresses glycolysis, and reduces cisplatin resistance, linking ULK2 to metabolic control of chemoresistance.","evidence":"Phosphoproteomics after ULK2 overexpression in ovarian cancer organoids with c-Jun phosphosite validation, glycolysis/chemosensitivity assays, and c-Jun rescue","pmids":["41719166"],"confidence":"Medium","gaps":["Overexpression-based, endogenous role untested","Mechanism of c-Jun degradation downstream of Ser243 unclear","Single lab"]},{"year":null,"claim":"How ULK2 selects between its canonical autophagy-initiation role and its diverse autophagy-independent substrates (VCP, TBK1, PXN, CARMA2sh, c-Jun) in a tissue- and stimulus-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate selection or context-specificity","Structural basis of ULK2-specific versus ULK1-specific functions unknown","Endogenous physiological hierarchy of ULK2 substrates undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8,11,13,15,19]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,11,13,15,19]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2,6,12,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9,16]}],"complexes":["ULK2-FIP200-Atg13 autophagy initiation complex"],"partners":["FIP200","ATG13","KCTD12","KAPΒ2","VCP","TBK1","PXN","CARMA2SH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYT8","full_name":"Serine/threonine-protein kinase ULK2","aliases":["Unc-51-like kinase 2"],"length_aa":1036,"mass_kda":112.7,"function":"Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK, also acts as a negative regulator of AMPK through phosphorylation of the AMPK subunits PRKAA1, PRKAB2 and PRKAG1. May phosphorylate ATG13/KIAA0652, FRS2, FRS3 and RPTOR; however such data need additional evidences. Not involved in ammonia-induced autophagy or in autophagic response of cerebellar granule neurons (CGN) to low potassium concentration. Plays a role early in neuronal differentiation and is required for granule cell axon formation: may govern axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons","subcellular_location":"Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q8IYT8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ULK2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATG101","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ULK2","total_profiled":1310},"omim":[{"mim_id":"615089","title":"AUTOPHAGY-RELATED PROTEIN 101; ATG101","url":"https://www.omim.org/entry/615089"},{"mim_id":"615088","title":"AUTOPHAGY-RELATED 13; ATG13","url":"https://www.omim.org/entry/615088"},{"mim_id":"608650","title":"UNC51-LIKE AUTOPHAGY-ACTIVATING KINASE 2; ULK2","url":"https://www.omim.org/entry/608650"},{"mim_id":"604261","title":"AUTOPHAGY-RELATED 5; ATG5","url":"https://www.omim.org/entry/604261"},{"mim_id":"603168","title":"UNC51-LIKE AUTOPHAGY-ACTIVATING KINASE 1; ULK1","url":"https://www.omim.org/entry/603168"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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ULK2 shares domain architecture (N-terminal kinase domain, central PS domain, C-terminal domain) with ULK1 and C. elegans UNC-51. Chimeric ULK2/UNC-51 constructs showed kinase and PS domain functions are conserved across species while the C domain acts in a species-specific manner.\",\n \"method\": \"In vitro kinase autophosphorylation assay with truncation mutants; ULK2/UNC-51 chimeric constructs expressed in COS7 cells; C. elegans rescue assay\",\n \"journal\": \"Oncogene\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay with mutagenesis/truncation, single lab, no replication\",\n \"pmids\": [\"10557072\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2011,\n \"finding\": \"ULK1 and ULK2 are functionally redundant serine/threonine kinases required for autophagy induction under amino acid deprivation in MEFs; double knockout of ULK1 and ULK2 blocks amino acid starvation-induced autophagy but not glucose-deprivation-induced autophagy. Ammonia-induced autophagy proceeds independently of ULK1/ULK2.\",\n \"method\": \"Genetic double knockout (Ulk1/2-/- MEFs); autophagy readouts (LC3 conversion, electron microscopy)\",\n \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — clean genetic double KO with multiple autophagy readouts, replicated by independent labs\",\n \"pmids\": [\"21690395\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2011,\n \"finding\": \"ULK1 and ULK2 are functionally redundant in mediating starvation-induced autophagy in fibroblasts, but ULK1 (not ULK2) is specifically required for autophagy in cerebellar granule neurons responding to low potassium, demonstrating cell-type-specific non-redundancy.\",\n \"method\": \"Single and double knockout MEFs and cerebellar granule neurons; autophagy assays (LC3-II levels, autophagosome formation)\",\n \"journal\": \"Autophagy\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in two distinct cell types with specific phenotypic readouts, consistent with other KO studies\",\n \"pmids\": [\"21460635\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2011,\n \"finding\": \"Atg13-dependent autophagy induction can proceed independently of ULK1 and ULK2; simultaneous Ulk1/Ulk2 double knockout did not phenocopy Atg13 deficiency, and ULK1-dependent phosphorylation sites in Atg13 were found dispensable for autophagy induction.\",\n \"method\": \"Ulk1/2 double knockout cells; Atg13-deficient cells; phosphorylation site mutagenesis\",\n \"journal\": \"Autophagy\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double KO and mutagenesis, single lab\",\n \"pmids\": [\"22024743\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2011,\n \"finding\": \"Ulk2 promotes neuropil elaboration in zebrafish habenular neurons, and this activity is asymmetrically inhibited by Kctd12.1, which physically interacts with Ulk2. Knockdown of Ulk2 reduces asymmetric neuropil elaboration; overexpression causes excess neuropil. This interaction was identified through a screen for Kctd12.1-interacting proteins.\",\n \"method\": \"Protein interaction screen; zebrafish knockdown and overexpression; morphological analysis of habenular neuropil\",\n \"journal\": \"The Journal of neuroscience\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — interaction screen plus functional gain/loss-of-function in zebrafish, single lab\",\n \"pmids\": [\"21734278\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2013,\n \"finding\": \"ULK2 knockdown in differentiated 3T3-L1 adipocytes reduces basal and mTORC1 inhibition-induced autophagy, reduces basal lipolysis, reduces mitochondrial respiration, and has opposing effects to ULK1 knockdown on fatty acid oxidation and fatty acid uptake, indicating functionally distinct roles for ULK1 and ULK2 in lipid metabolism.\",\n \"method\": \"shRNA knockdown of Ulk1 and Ulk2 in differentiated 3T3-L1 adipocytes; lipolysis assays; Seahorse metabolic flux analysis; autophagy assays\",\n \"journal\": \"Autophagy\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with multiple metabolic readouts, single lab, two orthogonal functional assays\",\n \"pmids\": [\"24135897\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2014,\n \"finding\": \"ULK2 overexpression induces autophagy and inhibits growth of glioma cells; this growth inhibition requires kinase activity (kinase-dead mutant fails to induce autophagy or inhibit growth) and is autophagy-dependent (abolished in ATG5-/- cells). ULK2 also inhibits anchorage-independent growth and astrocyte transformation in vitro and tumor growth in vivo.\",\n \"method\": \"Ectopic overexpression of wild-type and kinase-dead ULK2; ATG5+/+ and ATG5-/- iBMK cells; autophagy assays; anchorage-independent growth assay; in vivo xenograft\",\n \"journal\": \"The Journal of biological chemistry\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — active-site mutagenesis with genetic epistasis using ATG5 KO, single lab\",\n \"pmids\": [\"24923441\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2015,\n \"finding\": \"ULK2 is transported into the nucleus via karyopherin beta 2 (Kapβ2) through a PY-NLS motif (residues 774-795) in its S/P spacer domain. PKA phosphorylation of ULK2 at Ser1027 promotes nuclear localization, functional dissociation from Atg13 and FIP200, and reduced autophagic activity. Mutation of the Kapβ2-binding motif (P794A) retained ULK2 in the cytoplasm and increased autophagy activity.\",\n \"method\": \"In vitro and in vivo pull-down of ULK2 with Kapβ2; confocal co-localization; site-directed mutagenesis (P794A, Ser1027); autophagy activity assay; in vitro kinase assay\",\n \"journal\": \"PloS one\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down, mutagenesis, and localization with functional consequence, single lab\",\n \"pmids\": [\"26052940\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2017,\n \"finding\": \"ULK2 binds to and phosphorylates CARMA2sh in human keratinocytes, thereby inhibiting CARMA2sh-mediated NF-κB activation by promoting lysosomal degradation of BCL10. Psoriasis-associated missense mutations in CARMA2sh escape ULK2-mediated phosphorylation and inhibition.\",\n \"method\": \"Co-immunoprecipitation; in vitro kinase assay; NF-κB reporter assay; lysosomal degradation assay; psoriasis mutant analysis\",\n \"journal\": \"Cell death & disease\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vitro kinase assay plus functional NF-κB readout, single lab\",\n \"pmids\": [\"28230860\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2017,\n \"finding\": \"ULK1 and ULK2 are required for proper axon guidance and defasciculation in the developing mouse forebrain (corpus callosum, anterior commissure, corticothalamic and thalamocortical axons) via an autophagy-independent pathway, as these defects were not recapitulated by loss of Atg7 or Rb1cc1.\",\n \"method\": \"CNS-specific conditional Ulk1/2 double knockout mice (Nes-Cre); Atg7 and Rb1cc1 knockout comparison; brain histology; axon tracing\",\n \"journal\": \"Autophagy\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — conditional double KO with genetic epistasis using multiple autophagy gene KOs, multiple orthogonal anatomical readouts\",\n \"pmids\": [\"29099309\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2018,\n \"finding\": \"Ulk2 heterozygous loss in mice leads to p62 upregulation in prefrontal cortex pyramidal neurons, reduced GABAA receptor surface expression, and excitatory-inhibitory imbalance. Reducing p62 genetically or pharmacologically, or blocking p62-GABARAPL2 interaction with a peptide, restores GABAA receptor surface expression and rescues behavioral deficits, placing ULK2 upstream of p62-mediated regulation of GABAA receptor endocytic trafficking.\",\n \"method\": \"Ulk2+/- mice; immunofluorescence; electrophysiology; receptor surface expression assay; genetic p62 reduction; peptide interference; behavioral tests\",\n \"journal\": \"Human molecular genetics\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic, pharmacological, peptide interference) with rescue of cellular and behavioral phenotypes, single lab\",\n \"pmids\": [\"29893844\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2019,\n \"finding\": \"ULK1 and ULK2 localize to stress granules, phosphorylate VCP/p97, and thereby increase VCP's ATPase activity and ability to disassemble stress granules. Loss of ULK1/2 in mice causes vacuolar myopathy with ubiquitin- and TDP-43-positive inclusions similar to VCP mutation-associated inclusion body myopathy.\",\n \"method\": \"Ulk1/2 double knockout mouse model; co-localization of ULK1/2 with stress granule markers; in vitro phosphorylation of VCP; VCP ATPase activity assay; stress granule disassembly assay; ULK1/2 agonist treatment\",\n \"journal\": \"Molecular cell\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay on VCP substrate plus functional stress granule disassembly readout plus in vivo KO phenotype, multiple orthogonal methods\",\n \"pmids\": [\"30979586\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2019,\n \"finding\": \"ULK2 (but not ULK1) is specifically required in skeletal muscle for basal selective degradation of insoluble ubiquitinated protein aggregates associated with p62 and NBR1. ULK2 deficiency causes accumulation of these aggregates, myofiber atrophy, and degeneration without impairing autophagy initiation, autophagosome-lysosome fusion, or proteasome/lysosome protease activities.\",\n \"method\": \"Muscle-specific ULK2 and ULK1 knockout mice; ubiquitinated protein aggregate fractionation; p62/NBR1 immunostaining; muscle force measurements; lysosome and proteasome activity assays\",\n \"journal\": \"FASEB journal\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — paralog-specific KO with multiple orthogonal biochemical and functional readouts distinguishing ULK2 from ULK1\",\n \"pmids\": [\"31361156\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2021,\n \"finding\": \"PKCλ/ι directly phosphorylates ULK2, repressing its activity and promoting its degradation via an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι increases enzymatically active ULK2, which then directly phosphorylates and activates TBK1 to stimulate STING-mediated interferon signaling.\",\n \"method\": \"In vitro kinase assay (PKCλ/ι phosphorylates ULK2); in vitro kinase assay (ULK2 phosphorylates TBK1); PKCλ/ι knockout and pharmacological inhibition; ULK2 degradation assay; STING pathway reporter; CD8+ T cell recruitment in tumor models\",\n \"journal\": \"Molecular cell\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assays for both upstream (PKCλ/ι→ULK2) and downstream (ULK2→TBK1) steps with in vivo functional validation\",\n \"pmids\": [\"34560002\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"Perinatal loss of ULK2 in cardiomyocytes (cU2-KO) enhances basal autophagy dependent on the remaining ULK1, preserving cardiac function. Perinatal double loss of ULK1 and ULK2 impairs autophagy causing age-related cardiomyopathy. Adult-specific loss of ULK2 (icU2-KO) does not cause cardiomyopathy, distinguishing its developmental role from that of ULK1.\",\n \"method\": \"Cardiomyocyte-specific and inducible ULK1 and ULK2 knockout mice; autophagy flux assays; cardiac function (echocardiography); mitochondrial respiration; survival analysis\",\n \"journal\": \"Autophagy\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models (single, double, inducible) with orthogonal cardiac and autophagy readouts\",\n \"pmids\": [\"35104184\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"ULK1 and ULK2 phosphorylate the focal adhesion protein paxillin (PXN) at serine residues, inhibiting focal adhesion assembly and F-actin organization to suppress breast cancer cell migration in an autophagy-independent manner. ULK1/2-mediated serine phosphorylation of PXN counteracts tyrosine phosphorylation by PTK2 and SRC.\",\n \"method\": \"ULK1/2 kinase assay on PXN; phosphorylation site mapping; focal adhesion and F-actin imaging; migration assays; autophagy-deficient control conditions\",\n \"journal\": \"Autophagy\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay on identified substrate with functional migration readout, single lab\",\n \"pmids\": [\"38163960\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2014,\n \"finding\": \"Ulk2 interacts with Kctd12 proteins via its proline/serine-rich domain, and this interaction negatively regulates Ulk2-driven dendrite branching and elaboration in zebrafish habenular neurons. Loss of Kctd12 results in excess branching; loss of Ulk2 reduces dendrite elaboration and increases anxiety-like behavior.\",\n \"method\": \"Protein interaction mapping (Kctd12-Ulk2 domain interaction); zebrafish loss-of-function (morpholino/mutant); dendritic morphology quantification; behavioral assays\",\n \"journal\": \"PloS one\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped interaction with reciprocal loss-of-function phenotypes, single lab\",\n \"pmids\": [\"25329151\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"ULK2 forms a stable complex with FIP200, which in turn specifically interacts with AMPK α1 and γ1 subunits (but not other AMPK subunits). shRNA-mediated knockdown of ULK2 activates AMPK and promotes cytoplasmic accumulation of ULK1 and FIP200, thereby inducing autophagy-dependent degradation of BCR::ABL and CML cell death.\",\n \"method\": \"Mass spectrometry analysis of ULK2 complex in 293FT cells; shRNA knockdown of ULK2 in CML cells; AMPK activation assay; ULK1/FIP200 localization; BCR::ABL degradation assay; cell viability\",\n \"journal\": \"Biochemical and biophysical research communications\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry complex identification plus shRNA KD with multiple functional readouts, single lab\",\n \"pmids\": [\"40664084\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"METTL3-mediated m6A modification of ULK2 mRNA upregulates ULK2 expression in hypertrophic scar fibroblasts, enhancing autophagy and driving fibroblast-to-myofibroblast differentiation. Silencing METTL3 impaired autophagic flux and inhibited this differentiation.\",\n \"method\": \"MeRIP-seq to identify m6A sites on ULK2 mRNA; METTL3 siRNA knockdown; Western blotting; transmission electron microscopy; LC3-II/I ratio; in vivo siRNA injection in rabbit ear HS model\",\n \"journal\": \"International journal of biological macromolecules\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus KD with multiple orthogonal readouts including in vivo model, single lab\",\n \"pmids\": [\"40409645\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2026,\n \"finding\": \"ULK2 overexpression in cisplatin-resistant ovarian cancer organoids phosphorylates c-Jun at Ser243, promoting c-Jun degradation and suppressing glycolysis, thereby reducing cisplatin resistance. c-Jun overexpression counteracts both the chemosensitivity and glycolytic suppression induced by ULK2.\",\n \"method\": \"Phosphoproteomics after ULK2 overexpression in organoids; c-Jun phosphorylation validation; glycolysis assays; CCK-8 and in vivo experiments; c-Jun overexpression rescue\",\n \"journal\": \"Science progress\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 1 / Moderate — phosphoproteomics-identified substrate (c-Jun Ser243) with rescue experiment and functional glycolysis/chemosensitivity readouts, single lab\",\n \"pmids\": [\"41719166\"],\n \"is_preprint\": false\n }\n ],\n \"current_model\": \"ULK2 is a serine/threonine kinase that autophosphorylates in its PS domain and functions as a mammalian ATG1/UNC-51 ortholog: it forms a complex with FIP200 and Atg13 to initiate autophagy under nutrient stress (redundantly with ULK1 in most cell types, but with tissue-specific unique roles in skeletal muscle and the adult heart); it is negatively regulated by PKCλ/ι phosphorylation (promoting its microautophagic degradation) and by PKA-dependent Ser1027 phosphorylation (driving nuclear import via Kapβ2/PY-NLS and dissociation from Atg13/FIP200); when active, ULK2 phosphorylates downstream substrates including VCP/p97 (promoting stress granule disassembly), TBK1 (activating STING-mediated interferon signaling), paxillin/PXN (inhibiting focal adhesion assembly and cell migration), CARMA2sh (suppressing NF-κB via BCL10 lysosomal degradation), and c-Jun (Ser243, suppressing glycolysis); ULK2 also regulates GABAA receptor surface expression in cortical pyramidal neurons through autophagic control of p62, and promotes neuropil/dendrite elaboration in habenular neurons through interaction with Kctd12.\"\n}\n```","stage2_raw":"{\n \"mechanistic_narrative\": \"ULK2 is a serine/threonine kinase that initiates and directs autophagy as the mammalian counterpart of ATG1/UNC-51, sharing an N-terminal kinase domain, central proline/serine-rich (PS) domain, and C-terminal domain with ULK1, and undergoing autophosphorylation within the PS domain [#0]. Together with its paralog ULK1, ULK2 is required for amino-acid-starvation-induced autophagy and the two kinases are largely functionally redundant in fibroblasts, yet they diverge in a cell-type-specific manner, with ULK2 carrying unique roles in skeletal muscle, the developing heart, and lipid metabolism [#1, #2, #12, #14]. Beyond canonical autophagy initiation, ULK2 acts through autophagy-independent kinase functions on a growing set of substrates: it phosphorylates VCP/p97 to drive stress-granule disassembly [#11], activates TBK1 to stimulate STING-mediated interferon signaling [#13], phosphorylates paxillin/PXN to oppose focal adhesion assembly and suppress cell migration [#15], phosphorylates CARMA2sh to restrain NF-\\u03baB activation via lysosomal degradation of BCL10 [#8], and phosphorylates c-Jun at Ser243 to suppress glycolysis [#19]. ULK2 activity is negatively controlled by PKC\\u03bb/\\u03b9, which phosphorylates it to promote endosomal microautophagy-driven degradation [#13], and by PKA-dependent Ser1027 phosphorylation, which drives Kap\\u03b22/PY-NLS-mediated nuclear import and dissociation from Atg13 and FIP200 [#7]. In the nervous system, ULK2 governs habenular neuropil and dendrite elaboration through interaction with Kctd12 [#4, #16], and regulates GABAA receptor surface expression in cortical pyramidal neurons upstream of p62 [#10]. Functionally, ULK2 acts as a growth suppressor in glioma and modulates chemoresistance, consistent with a broad tumor-suppressive role [#6, #19].\",\n \"teleology\": [\n {\n \"year\": 1999,\n \"claim\": \"Established ULK2 as an autophosphorylating serine/threonine kinase with a conserved ATG1/UNC-51-type domain architecture, defining the structural basis for its catalytic activity.\",\n \"evidence\": \"In vitro kinase autophosphorylation assays with truncation mutants and ULK2/UNC-51 chimeras in COS7 cells plus C. elegans rescue\",\n \"pmids\": [\"10557072\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"No physiological substrate identified at this stage\", \"Cellular function not addressed\", \"Single lab, no replication\"]\n },\n {\n \"year\": 2011,\n \"claim\": \"Defined ULK1/ULK2 redundancy in starvation-induced autophagy while revealing both stimulus-specificity and cell-type-specific non-redundancy, refining when ULK2 is functionally required.\",\n \"evidence\": \"Single and double Ulk1/2 knockout MEFs and cerebellar granule neurons with LC3/EM autophagy readouts\",\n \"pmids\": [\"21690395\", \"21460635\", \"22024743\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Does not resolve molecular basis of ULK2-specific versus ULK1-specific roles\", \"Atg13-independent autophagy mechanism unexplained\", \"Glucose- and ammonia-induced autophagy pathways unmapped\"]\n },\n {\n \"year\": 2011,\n \"claim\": \"Identified ULK2 as a regulator of habenular neuropil elaboration, linking the kinase to neuronal morphogenesis through a Kctd12 interaction.\",\n \"evidence\": \"Kctd12.1 interaction screen with zebrafish knockdown/overexpression and habenular morphology analysis\",\n \"pmids\": [\"21734278\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Kinase substrates in this pathway unidentified\", \"Mechanism of Kctd12-mediated inhibition unknown\", \"Autophagy-dependence not tested\"]\n },\n {\n \"year\": 2013,\n \"claim\": \"Distinguished ULK2 from ULK1 in adipocyte lipid metabolism, showing the paralogs can exert opposing metabolic effects.\",\n \"evidence\": \"shRNA knockdown in 3T3-L1 adipocytes with lipolysis, Seahorse flux, and autophagy assays\",\n \"pmids\": [\"24135897\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Substrates underlying metabolic effects unknown\", \"Knockdown rather than clean genetic deletion\", \"Mechanism of opposing ULK1/ULK2 effects unresolved\"]\n },\n {\n \"year\": 2014,\n \"claim\": \"Established ULK2 as a kinase-dependent, autophagy-dependent growth suppressor in glioma, connecting its catalytic activity to tumor suppression.\",\n \"evidence\": \"Wild-type versus kinase-dead overexpression in ATG5+/+ and ATG5-/- cells with growth and xenograft assays\",\n \"pmids\": [\"24923441\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Overexpression-based, endogenous role untested\", \"Relevant substrates not identified\", \"Single lab\"]\n },\n {\n \"year\": 2014,\n \"claim\": \"Mapped the Kctd12-ULK2 interaction to the PS domain and tied it to dendrite elaboration and anxiety-like behavior, deepening the neuronal morphogenesis role.\",\n \"evidence\": \"Domain-mapped interaction with zebrafish loss-of-function and dendrite/behavioral quantification\",\n \"pmids\": [\"25329151\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Kinase activity requirement not established\", \"Downstream effectors unknown\", \"Single lab\"]\n },\n {\n \"year\": 2015,\n \"claim\": \"Revealed PKA-driven, Kap\\u03b22/PY-NLS-mediated nuclear import as a switch that dissociates ULK2 from Atg13/FIP200 and dampens autophagy, providing a regulatory off-switch.\",\n \"evidence\": \"Reciprocal Kap\\u03b22 pull-down, confocal co-localization, P794A/Ser1027 mutagenesis, and autophagy assays\",\n \"pmids\": [\"26052940\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Nuclear function of ULK2 undefined\", \"PKA upstream signal context unmapped\", \"Single lab\"]\n },\n {\n \"year\": 2017,\n \"claim\": \"Identified CARMA2sh as a ULK2 substrate, linking the kinase to NF-\\u03baB suppression and psoriasis-associated signaling.\",\n \"evidence\": \"Co-IP, in vitro kinase assay, NF-\\u03baB reporter, lysosomal degradation assay, and psoriasis mutant analysis\",\n \"pmids\": [\"28230860\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Phosphosite on CARMA2sh not pinpointed in narrative\", \"In vivo relevance untested\", \"Single lab\"]\n },\n {\n \"year\": 2017,\n \"claim\": \"Demonstrated an autophagy-independent requirement for ULK1/ULK2 in forebrain axon guidance, establishing non-autophagic functions in CNS development.\",\n \"evidence\": \"Nes-Cre conditional Ulk1/2 double knockout mice with Atg7/Rb1cc1 epistasis and axon tracing\",\n \"pmids\": [\"29099309\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Substrates mediating axon guidance unknown\", \"ULK2-specific contribution not separated from ULK1\", \"Mechanism of guidance unresolved\"]\n },\n {\n \"year\": 2018,\n \"claim\": \"Placed ULK2 upstream of p62-mediated GABAA receptor trafficking, linking its loss to excitatory-inhibitory imbalance and behavioral deficits.\",\n \"evidence\": \"Ulk2+/- mice with electrophysiology, receptor surface assays, genetic/pharmacological/peptide p62 rescue, and behavior\",\n \"pmids\": [\"29893844\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Direct ULK2 substrate in this pathway unidentified\", \"Connection to canonical autophagy machinery not fully defined\", \"Single lab\"]\n },\n {\n \"year\": 2019,\n \"claim\": \"Identified VCP/p97 as a ULK1/ULK2 substrate driving stress granule disassembly, and skeletal-muscle ULK2 as required for selective clearance of ubiquitinated aggregates, defining proteostatic functions.\",\n \"evidence\": \"Ulk1/2 double KO and muscle-specific paralog-specific KO mice with in vitro VCP phosphorylation, ATPase/disassembly assays, and aggregate fractionation\",\n \"pmids\": [\"30979586\", \"31361156\"],\n \"confidence\": \"High\",\n \"gaps\": [\"VCP phosphosite mapping limited\", \"How ULK2 selectively recognizes aggregates unknown\", \"Relationship to autophagosome formation in muscle not fully resolved\"]\n },\n {\n \"year\": 2021,\n \"claim\": \"Defined a complete upstream-downstream signaling axis: PKC\\u03bb/\\u03b9 represses and degrades ULK2 via endosomal microautophagy, while active ULK2 phosphorylates TBK1 to drive STING interferon signaling and antitumor immunity.\",\n \"evidence\": \"In vitro kinase assays for both PKC\\u03bb/\\u03b9\\u2192ULK2 and ULK2\\u2192TBK1 steps with PKC\\u03bb/\\u03b9 KO/inhibition, STING reporter, and CD8+ T cell tumor models\",\n \"pmids\": [\"34560002\"],\n \"confidence\": \"High\",\n \"gaps\": [\"TBK1 phosphosite not detailed\", \"Balance between ULK2 autophagic and immune functions unclear\", \"Single lab\"]\n },\n {\n \"year\": 2022,\n \"claim\": \"Separated developmental from adult cardiac roles, showing perinatal but not adult ULK2 loss is compensated by ULK1, clarifying tissue- and timing-specific essentiality.\",\n \"evidence\": \"Cardiomyocyte-specific, double, and inducible KO mice with autophagy flux, echocardiography, and mitochondrial respiration\",\n \"pmids\": [\"35104184\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Molecular basis of developmental versus adult difference unknown\", \"ULK2-unique substrates in heart unidentified\"]\n },\n {\n \"year\": 2024,\n \"claim\": \"Identified paxillin as a ULK1/ULK2 substrate whose serine phosphorylation opposes focal adhesion assembly and PTK2/SRC tyrosine signaling, defining an autophagy-independent role in migration.\",\n \"evidence\": \"In vitro kinase assay on PXN, phosphosite mapping, focal adhesion/F-actin imaging, and migration assays with autophagy-deficient controls\",\n \"pmids\": [\"38163960\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"In vivo relevance for metastasis untested\", \"ULK2-specific versus ULK1 contribution not separated\", \"Single lab\"]\n },\n {\n \"year\": 2025,\n \"claim\": \"Resolved a stable ULK2-FIP200 complex that links to AMPK \\u03b11/\\u03b31 subunits and showed ULK2 loss activates AMPK to promote autophagic BCR::ABL degradation, extending ULK2 regulation to leukemia.\",\n \"evidence\": \"Mass spectrometry of the ULK2 complex in 293FT cells with shRNA knockdown, AMPK activation, localization, and BCR::ABL degradation assays in CML cells\",\n \"pmids\": [\"40664084\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Direction of AMPK-ULK2 regulation incompletely defined\", \"Knockdown rather than genetic deletion\", \"Single lab\"]\n },\n {\n \"year\": 2025,\n \"claim\": \"Showed METTL3-mediated m6A modification upregulates ULK2 to enhance autophagy and drive fibroblast-to-myofibroblast differentiation, identifying an upstream transcript-level control of ULK2.\",\n \"evidence\": \"MeRIP-seq, METTL3 siRNA knockdown, autophagy readouts, and in vivo rabbit ear hypertrophic scar model\",\n \"pmids\": [\"40409645\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"m6A reader mediating ULK2 upregulation unidentified\", \"Direct kinase substrates in fibrosis unknown\", \"Single lab\"]\n },\n {\n \"year\": 2026,\n \"claim\": \"Identified c-Jun Ser243 as a ULK2 substrate whose phosphorylation promotes c-Jun degradation, suppresses glycolysis, and reduces cisplatin resistance, linking ULK2 to metabolic control of chemoresistance.\",\n \"evidence\": \"Phosphoproteomics after ULK2 overexpression in ovarian cancer organoids with c-Jun phosphosite validation, glycolysis/chemosensitivity assays, and c-Jun rescue\",\n \"pmids\": [\"41719166\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Overexpression-based, endogenous role untested\", \"Mechanism of c-Jun degradation downstream of Ser243 unclear\", \"Single lab\"]\n },\n {\n \"year\": null,\n \"claim\": \"How ULK2 selects between its canonical autophagy-initiation role and its diverse autophagy-independent substrates (VCP, TBK1, PXN, CARMA2sh, c-Jun) in a tissue- and stimulus-specific manner remains unresolved.\",\n \"evidence\": \"\",\n \"pmids\": [],\n \"confidence\": \"Medium\",\n \"gaps\": [\"No unifying model for substrate selection or context-specificity\", \"Structural basis of ULK2-specific versus ULK1-specific functions unknown\", \"Endogenous physiological hierarchy of ULK2 substrates undefined\"]\n }\n ],\n \"mechanism_profile\": {\n \"molecular_activity\": [\n {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 11, 13, 15, 19]},\n {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 11, 13, 15, 19]},\n {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n ],\n \"localization\": [\n {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 11]},\n {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n ],\n \"pathway\": [\n {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2, 6, 12, 14]},\n {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 12]},\n {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 13]},\n {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 15]},\n {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9, 16]}\n ],\n \"complexes\": [\n \"ULK2-FIP200-Atg13 autophagy initiation complex\"\n ],\n \"partners\": [\n \"FIP200\",\n \"Atg13\",\n \"Kctd12\",\n \"Kap\\u03b22\",\n \"VCP\",\n \"TBK1\",\n \"PXN\",\n \"CARMA2sh\"\n ],\n \"other_free_text\": []\n }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}