{"gene":"ULK2","run_date":"2026-04-28T21:43:01","timeline":{"discoveries":[{"year":1999,"finding":"ULK2 is a serine/threonine kinase that undergoes autophosphorylation in vitro; truncation mutants identified the proline/serine-rich (PS) domain as the site of autophosphorylation. Domain chimera analysis with C. elegans UNC-51 showed that kinase and PS domain functions are conserved across species, while the C-terminal domain acts in a species-specific manner.","method":"In vitro autophosphorylation assay with truncation mutants; ULK2/UNC-51 chimeric kinase rescue experiments in C. elegans","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis/truncation analysis and chimeric rescue experiments","pmids":["10557072"],"is_preprint":false},{"year":2011,"finding":"ULK1 and ULK2 are functionally redundant kinases required for autophagy in response to amino acid (nitrogen) deprivation in fibroblasts, but not for autophagy induced by glucose deprivation or ammonia. In cerebellar granule neurons, ULK1 but not ULK2 is required for the autophagic response to low potassium, demonstrating cell-type-specific redundancy.","method":"Double knockout MEFs (Ulk1/2-/-) and single knockout analysis; autophagy assays under nutrient deprivation; genetic epistasis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — clean double KO with defined cellular phenotype, replicated across two papers (PMID 21460635, 21690395)","pmids":["21460635","21690395"],"is_preprint":false},{"year":2011,"finding":"Atg13 and FIP200 form a complex with ULK1/2, but Atg13 has autophagy-inducing functions independent of ULK1/2 kinase activity; simultaneous knockout of Ulk1 and Ulk2 did not fully recapitulate the autophagy defect of Atg13 loss, indicating Atg13 acts upstream in a ULK1/2-independent manner as well.","method":"Atg13-deficient cells combined with Ulk1/Ulk2 double knockout; autophagy induction assays; identification of Ulk1-dependent phosphorylation sites on Atg13","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — epistasis with multiple KO lines and phosphosite mapping","pmids":["22024743"],"is_preprint":false},{"year":2011,"finding":"In zebrafish, Ulk2 promotes neuropil elaboration in habenular neurons. Kctd12.1 was identified as a novel binding partner of Ulk2 (via protein interaction screen) that asymmetrically inhibits Ulk2 activity, causing left-right differences in habenular neuropil formation. Knockdown of Ulk2 reduces neuropil elaboration; overexpression causes excess elaboration.","method":"Screen for Kctd12.1-interacting proteins uncovering Ulk2 interaction; morpholino knockdown and overexpression in zebrafish; genetic mutation of kctd12","journal":"The Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2/3 — protein interaction plus loss- and gain-of-function in zebrafish ortholog, single lab","pmids":["21734278"],"is_preprint":false},{"year":2013,"finding":"In 3T3-L1 adipocytes, ULK2 knockdown reduces basal autophagy and mitochondrial respiration, and has opposing effects on fatty acid oxidation and uptake compared to ULK1, demonstrating distinct (non-redundant) roles of ULK1 and ULK2 in lipid metabolism.","method":"shRNA knockdown of Ulk1 and Ulk2 in differentiated adipocytes; lipolysis assays, fatty acid oxidation/uptake, mitochondrial respiration measurements","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple metabolic readouts, single lab","pmids":["24135897"],"is_preprint":false},{"year":2014,"finding":"ULK2 overexpression induces autophagy and inhibits glioma cell growth; a kinase-dead mutant of ULK2 fails to induce autophagy and fails to inhibit growth. Growth inhibition requires the autophagy-inducing activity of ULK2 (demonstrated in ATG5+/+ but not ATG5-/- cells).","method":"Ectopic overexpression of wild-type vs. kinase mutant ULK2; autophagy assays; ATG5-/- cells; in vivo tumor growth","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — active-site mutagenesis combined with ATG5 genetic epistasis and in vivo validation","pmids":["24923441"],"is_preprint":false},{"year":2015,"finding":"ULK2 is transported to the nucleus via karyopherin beta 2 (Kapβ2) through a PY-NLS motif ((774)GPGFGSSPPGAEAAPSLRYVPY(795)) in its S/P domain. PKA phosphorylates ULK2 at Ser1027, which promotes dissociation from Atg13 and FIP200, nuclear localization, and reduced autophagic activity. The cytoplasmic-localization mutant (P794A) shows increased autophagy.","method":"Pull-down assay (in vitro and in vivo); confocal microscopy co-localization; mutagenesis of PY-NLS (P794A) and Ser1027; transient transfection autophagy assays; in vitro kinase assay","journal":"PLoS One","confidence":"High","confidence_rationale":"Tier 1/2 — mutagenesis, pull-down, co-localization, functional assays showing phosphorylation-dependent nuclear translocation and autophagy regulation","pmids":["26052940"],"is_preprint":false},{"year":2017,"finding":"In zebrafish, Ulk2 positively regulates dendrite branching and elaboration in habenular neurons via interaction with Kctd12 proteins through a proline-serine-rich domain. Loss of Kctd12 results in increased dendritogenesis and decreased anxiety behavior, establishing a Kctd12–Ulk2 regulatory axis in neural circuit development.","method":"Genetic loss-of-function (ulk2 morpholino, kctd12 mutants) and gain-of-function in zebrafish; behavioral assays; domain mapping of Ulk2–Kctd12 interaction","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis and domain mapping in zebrafish ortholog, single lab","pmids":["25329151"],"is_preprint":false},{"year":2017,"finding":"ULK1 and ULK2 regulate axon guidance and defasciculation in the developing mouse forebrain via an autophagy-independent mechanism. CNS-specific double knockout mice show corpus callosum, anterior commissure, and thalamocortical axon defects not observed in Atg7 or Rb1cc1 single-KO mice, placing ULK1/2 in a noncanonical pathway for axon guidance.","method":"CNS-specific conditional double-knockout mice (Nes-Cre); comparison with Atg7-/- and Rb1cc1-/- mice; neuroanatomical analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with genetic epistasis against autophagy-null mice, strong phenotypic evidence for autophagy-independent pathway","pmids":["29099309"],"is_preprint":false},{"year":2017,"finding":"ULK2 binds to and phosphorylates CARMA2sh, inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10 in human keratinocytes. Psoriasis-associated missense mutants of CARMA2sh escape ULK2-mediated phosphorylation and inhibition.","method":"Co-immunoprecipitation; phosphorylation assays; lysosomal degradation assays; NF-κB reporter assays; mutant CARMA2sh analysis in keratinocytes","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal binding and phosphorylation assays with disease-linked mutants, single lab","pmids":["28230860"],"is_preprint":false},{"year":2018,"finding":"ULK2 deficiency in pyramidal neurons leads to p62 accumulation and selective reduction of GABAA receptor surface expression, causing excitatory-inhibitory imbalance in the prefrontal cortex. Reducing p62 levels or blocking p62-GABARAPL2 (GABARAP-associated protein) interaction restored GABAA receptor surface expression and behavioral deficits.","method":"Ulk2 heterozygous mouse model; biochemical fractionation; immunofluorescence; behavioral assays; peptide interference with p62-GABARAPL2 interaction; genetic p62 dosage reduction","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO model with multiple orthogonal rescue approaches establishing mechanistic pathway","pmids":["29893844"],"is_preprint":false},{"year":2019,"finding":"ULK1 and ULK2 localize to stress granules and phosphorylate VCP/p97, increasing VCP's ATPase activity and its ability to disassemble stress granules. Loss of ULK1/2 in mice causes vacuolar myopathy with ubiquitin and TDP-43-positive inclusions resembling IBM caused by VCP mutations.","method":"Co-localization by imaging; in vitro phosphorylation assay of VCP by ULK1/2; VCP ATPase activity assay; Ulk1/2-/- mouse model with myopathy characterization; ULK1/2 agonist treatment","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro phosphorylation assay of VCP, enzymatic activity assay, in vivo KO model, and pharmacological validation","pmids":["30979586"],"is_preprint":false},{"year":2019,"finding":"ULK2 (but not ULK1) is highly enriched in skeletal muscle and is uniquely required for basal selective autophagy of insoluble ubiquitinated protein aggregates associated with p62/SQSTM1 and NBR1. ULK2 deficiency causes myofiber atrophy, degeneration, and impaired muscle force without globally impairing autophagosome formation or lysosomal function.","method":"Skeletal muscle-specific Ulk2 KO mice compared to Ulk1 KO; ubiquitinated protein aggregate accumulation assays; p62/NBR1 co-localization; muscle force measurements; autophagy flux assays","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple orthogonal readouts, comparison to ULK1 KO establishing specificity","pmids":["31361156"],"is_preprint":false},{"year":2021,"finding":"PKCλ/ι directly phosphorylates and represses ULK2, promoting its degradation via endosomal microautophagy through a ubiquitin-dependent mechanism. Loss of PKCλ/ι increases enzymatically active ULK2, which directly phosphorylates and activates TBK1 to stimulate STING-mediated interferon signaling and enhance anti-tumor CD8+ T cell recruitment.","method":"In vitro kinase assay (PKCλ/ι phosphorylating ULK2); co-immunoprecipitation; ULK2 in vitro phosphorylation of TBK1; endosomal microautophagy degradation assays; PKCλ/ι-KO mouse intestinal tumor model; single-cell multiplex imaging","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro kinase assays for both PKCλ/ι→ULK2 and ULK2→TBK1, mechanistic degradation studies, in vivo tumor model validation","pmids":["34560002"],"is_preprint":false},{"year":2022,"finding":"Perinatal loss of both ULK1 and ULK2 in cardiomyocytes impairs autophagy and causes age-related cardiomyopathy; perinatal loss of either alone enhances basal autophagy via compensatory upregulation of the remaining paralog. Adult-specific loss of ULK1 (but not ULK2) causes rapidly developing cardiomyopathy and heart failure with mitochondrial defects, indicating developmental-stage-specific functional differentiation.","method":"Cardiomyocyte-specific conditional KO mice (perinatal and inducible adult); autophagy flux assays; mitochondrial respiration; cardiac function measurements; trehalose rescue","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — multiple conditional KO models with orthogonal functional and biochemical readouts","pmids":["35104184"],"is_preprint":false},{"year":2024,"finding":"ULK1 and ULK2 inhibit focal adhesion assembly and F-actin formation by phosphorylating the adhesion protein paxillin (PXN), preventing breast cancer cell migration in an autophagy-independent manner. ULK1/2-mediated serine phosphorylation of PXN counteracts PTK2 (FAK) and SRC-mediated tyrosine phosphorylation at adjacent residues, gatekeeping mechanotransduction.","method":"In vitro phosphorylation assay of PXN; mutational analysis of PXN phosphosites; focal adhesion assembly imaging; F-actin quantification; cell migration assays with ULK1/2 KO/KD","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro phosphorylation assay with mutagenesis plus functional migration/adhesion readouts in autophagy-independent context","pmids":["38163960"],"is_preprint":false},{"year":2025,"finding":"ULK2 forms a stable complex with FIP200, which interacts specifically with AMPK α1 and γ1 subunits (identified by mass spectrometry). ShRNA-mediated knockdown of ULK2 in CML cells induces AMPK activation, promotes cytoplasmic accumulation of ULK1 and FIP200, and triggers autophagy-dependent degradation of BCR::ABL, leading to cell death.","method":"Mass spectrometry interactome analysis; co-immunoprecipitation; shRNA knockdown of ULK2 in 293FT and CML cells; autophagy flux and BCR::ABL degradation assays","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — MS-based complex identification plus KD with functional readouts, single lab","pmids":["40664084"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated N6-methyladenosine (m6A) modification upregulates ULK2 mRNA expression in hypertrophic scar fibroblasts, promoting autophagy and fibroblast-to-myofibroblast differentiation; silencing METTL3 impairs ULK2-driven autophagic flux and reduces scar formation in vivo.","method":"MeRIP-seq (m6A RNA immunoprecipitation sequencing); qRT-PCR; Western blotting; METTL3 siRNA knockdown; transmission electron microscopy; rabbit ear scar model","journal":"International Journal of Biological Macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP-seq identifies m6A modification site on ULK2 with functional KD validation in vitro and in vivo, single lab","pmids":["40409645"],"is_preprint":false},{"year":2025,"finding":"ULK2 overexpression in cisplatin-resistant ovarian cancer organoids suppresses glycolysis and restores chemosensitivity. Phosphoproteomics revealed ULK2 phosphorylates c-Jun at Ser243, promoting c-Jun degradation and reducing glycolytic gene expression; c-Jun overexpression counteracts ULK2-induced chemosensitivity and glycolysis suppression.","method":"Phosphoproteomics in ULK2-overexpressing organoids; CCK-8 and in vivo experiments; glycolysis assays; c-Jun overexpression rescue","journal":"Science Progress","confidence":"Medium","confidence_rationale":"Tier 2 — phosphoproteomics-identified substrate with functional rescue experiment, single lab, novel substrate","pmids":["41719166"],"is_preprint":false}],"current_model":"ULK2 is a serine/threonine kinase (with autophosphorylation in its PS domain) that, redundantly with ULK1, initiates canonical autophagy downstream of mTORC1 in response to amino acid deprivation by operating within an ATG13/FIP200/AMPK complex, while also performing autophagy-independent functions including phosphorylation of VCP/p97 to disassemble stress granules, phosphorylation of paxillin (PXN) to inhibit focal adhesion assembly and cell migration, phosphorylation of TBK1 to activate STING-mediated interferon signaling (itself regulated by PKCλ/ι-mediated phosphorylation and microautophagic degradation), phosphorylation of CARMA2sh to suppress NF-κB, phosphorylation of c-Jun to suppress glycolysis, regulation of GABAA receptor surface expression via autophagy-dependent p62 clearance, and promotion of axon guidance and dendritogenesis through noncanonical pathways, with its nuclear vs. cytoplasmic localization governed by PKA-mediated Ser1027 phosphorylation and Kapβ2-dependent nuclear import."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that ULK2 possesses intrinsic serine/threonine kinase activity with autophosphorylation in its PS domain, and that kinase/PS domain functions are evolutionarily conserved with C. elegans UNC-51, provided the foundational biochemical identity of ULK2 as an active kinase.","evidence":"In vitro autophosphorylation assays with truncation mutants and ULK2/UNC-51 chimeric rescue in C. elegans","pmids":["10557072"],"confidence":"High","gaps":["No mammalian in vivo substrates identified","Kinase regulation mechanisms unknown","Physiological role in mammalian cells untested"]},{"year":2011,"claim":"Demonstrating that ULK1 and ULK2 are functionally redundant for amino-acid-deprivation-induced autophagy but dispensable for glucose/ammonia-induced autophagy, and that they function within an ATG13–FIP200 complex with ATG13 retaining ULK-independent activity, defined the scope and limits of ULK2's canonical autophagy role.","evidence":"Ulk1/Ulk2 double-knockout MEFs; Atg13-deficient cells; multiple autophagy induction conditions","pmids":["21460635","21690395","22024743"],"confidence":"High","gaps":["Molecular basis of stimulus-specific autophagy pathway selectivity unknown","Relative contribution of ULK2 kinase activity vs. scaffolding unclear"]},{"year":2011,"claim":"Identification of Kctd12.1 as a ULK2-binding partner that asymmetrically inhibits ULK2 to generate left–right differences in habenular neuropil elaboration revealed a neurodevelopmental function for ULK2 beyond autophagy.","evidence":"Protein interaction screen and morpholino knockdown/overexpression in zebrafish","pmids":["21734278"],"confidence":"Medium","gaps":["Mechanism by which Kctd12 inhibits ULK2 kinase activity uncharacterized","Not confirmed in mammalian neurons at this stage","Direct phosphorylation substrate in this context unknown"]},{"year":2014,"claim":"Showing that ULK2's kinase activity is required for autophagy-dependent tumor growth inhibition in glioma (via ATG5 epistasis) established that ULK2 can function as a tumor suppressor through its autophagy-initiating activity.","evidence":"Kinase-dead ULK2 mutant; ATG5-null epistasis; in vivo tumor growth assays","pmids":["24923441"],"confidence":"High","gaps":["Downstream targets mediating growth suppression not identified","Whether this is ULK2-specific or shared with ULK1 not tested"]},{"year":2015,"claim":"Discovery that PKA phosphorylates ULK2 at Ser1027, causing dissociation from ATG13/FIP200 and Kapβ2-dependent nuclear import, revealed a phosphorylation switch governing ULK2 subcellular distribution and autophagy activity.","evidence":"Pull-down, confocal imaging, PY-NLS and Ser1027 mutagenesis, in vitro kinase assay","pmids":["26052940"],"confidence":"High","gaps":["Nuclear function of ULK2 unknown","Physiological stimuli that activate PKA-mediated nuclear import uncharacterized"]},{"year":2017,"claim":"CNS-specific Ulk1/Ulk2 double knockout in mice produced corpus callosum and axon guidance defects not seen in canonical autophagy knockouts (Atg7, Rb1cc1), establishing a bona fide autophagy-independent neurodevelopmental function for ULK1/2.","evidence":"Nestin-Cre conditional double KO mice compared with Atg7−/− and Rb1cc1−/− mice; neuroanatomical analysis","pmids":["29099309"],"confidence":"High","gaps":["Downstream effectors of ULK1/2 in axon guidance unidentified","Individual contributions of ULK1 vs. ULK2 to axon guidance not resolved"]},{"year":2017,"claim":"Identification of CARMA2sh as a direct ULK2 phosphorylation substrate that, when phosphorylated, promotes BCL10 lysosomal degradation and NF-κB suppression—with psoriasis-associated CARMA2sh mutants escaping this regulation—linked ULK2 to skin inflammatory disease mechanisms.","evidence":"Co-IP, phosphorylation assays, NF-κB reporter assays, disease-associated mutant analysis in keratinocytes","pmids":["28230860"],"confidence":"Medium","gaps":["Specific phosphorylation sites on CARMA2sh not mapped","Not independently replicated","In vivo relevance in psoriasis models untested"]},{"year":2018,"claim":"Demonstrating that ULK2 haploinsufficiency causes p62 accumulation that sequesters GABARAPL2 and reduces GABAA receptor surface levels in prefrontal cortex neurons, correctable by p62 reduction, established a specific mechanism linking ULK2 to excitatory–inhibitory balance.","evidence":"Ulk2 heterozygous mice; biochemical fractionation; peptide interference with p62–GABARAPL2; genetic p62 dosage reduction; behavioral assays","pmids":["29893844"],"confidence":"High","gaps":["Whether full ULK2 KO worsens the phenotype not shown","How p62–GABARAPL2 interaction specifically affects GABAA trafficking not fully resolved"]},{"year":2019,"claim":"Two studies revealed non-redundant tissue-specific functions: ULK1/2 phosphorylate VCP/p97 to enhance its ATPase activity and stress granule disassembly (with double-KO mice developing inclusion body myopathy), while ULK2 alone is uniquely required in skeletal muscle for selective autophagy of ubiquitinated protein aggregates.","evidence":"In vitro VCP phosphorylation and ATPase assays; Ulk1/2 double-KO myopathy model; skeletal muscle-specific Ulk2 KO with aggregate and force measurements","pmids":["30979586","31361156"],"confidence":"High","gaps":["Specific VCP phosphosites mediating stress granule disassembly not fully mapped","Mechanism of ULK2-specific selective autophagy in muscle uncharacterized","Whether ULK2 muscle function is kinase-dependent not directly tested"]},{"year":2021,"claim":"Establishing that PKCλ/ι phosphorylates ULK2 to promote its endosomal microautophagic degradation, and that stabilized ULK2 directly phosphorylates and activates TBK1 to drive STING-mediated interferon signaling and anti-tumor immunity, placed ULK2 at the nexus of autophagy, innate immunity, and tumor microenvironment regulation.","evidence":"In vitro kinase assays for PKCλ/ι→ULK2 and ULK2→TBK1; microautophagy degradation assays; PKCλ/ι-KO intestinal tumor model; multiplex imaging","pmids":["34560002"],"confidence":"High","gaps":["Specific phosphosites on ULK2 targeted by PKCλ/ι not fully characterized","Whether ULK2→TBK1 axis operates outside intestinal tumors untested"]},{"year":2022,"claim":"Perinatal cardiomyocyte-specific deletion showed compensatory upregulation between ULK1 and ULK2, while adult-specific loss of ULK1 but not ULK2 caused acute cardiomyopathy, demonstrating stage-dependent functional differentiation between the paralogs in the heart.","evidence":"Perinatal and inducible adult cardiomyocyte-specific conditional KO mice; autophagy flux; mitochondrial and cardiac function measurements","pmids":["35104184"],"confidence":"High","gaps":["Why adult ULK2 loss is tolerated in heart while ULK1 loss is not remains unexplained at molecular level"]},{"year":2024,"claim":"Discovery that ULK1/2 phosphorylate paxillin to antagonize FAK/SRC-mediated tyrosine phosphorylation and inhibit focal adhesion assembly revealed an autophagy-independent role in mechanotransduction and cell migration control.","evidence":"In vitro PXN phosphorylation; phosphosite mutagenesis; focal adhesion imaging; migration assays with ULK1/2 KO","pmids":["38163960"],"confidence":"High","gaps":["Relative contribution of ULK2 vs. ULK1 to PXN phosphorylation in vivo not resolved","Structural basis of antagonism between serine and tyrosine phosphorylation on PXN unknown"]},{"year":2025,"claim":"Identification of ULK2-specific interactions with AMPK α1/γ1 subunits via FIP200, and demonstration that ULK2 knockdown triggers AMPK activation and autophagy-dependent BCR::ABL degradation in CML cells, revealed a ULK2-specific scaffolding role in AMPK regulation with therapeutic implications.","evidence":"Mass spectrometry interactome; co-IP; shRNA knockdown in CML cells; autophagy flux and BCR::ABL degradation assays","pmids":["40664084"],"confidence":"Medium","gaps":["Direct vs. FIP200-mediated interaction with AMPK subunits not distinguished","Whether this mechanism operates in primary CML patient cells unknown","Single-lab finding awaiting independent confirmation"]},{"year":2025,"claim":"Phosphoproteomic identification of c-Jun Ser243 as a direct ULK2 substrate that upon phosphorylation undergoes degradation, suppressing glycolytic gene expression and restoring cisplatin sensitivity in ovarian cancer, expanded ULK2's substrate repertoire to metabolic transcription factors.","evidence":"Phosphoproteomics in ULK2-overexpressing organoids; glycolysis assays; c-Jun overexpression rescue; in vivo experiments","pmids":["41719166"],"confidence":"Medium","gaps":["In vitro kinase assay directly confirming ULK2 phosphorylation of c-Jun Ser243 not shown","Generalizability beyond cisplatin-resistant ovarian cancer untested","Single-lab finding"]},{"year":null,"claim":"Key unresolved questions include the identity and function of nuclear ULK2 substrates, the structural basis for substrate selectivity between ULK1 and ULK2, and how ULK2's autophagy-independent functions (axon guidance, focal adhesion regulation, innate immune signaling) are coordinated with its canonical autophagy role in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No nuclear substrates or functions identified despite demonstrated nuclear import","No structural model of ULK2 or ULK2-substrate complexes available","Mechanism of ULK2 specificity in selective muscle autophagy unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,9,11,13,15,18]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2,5,6,10,12,14,16,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,13,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]}],"complexes":["ULK2–ATG13–FIP200 complex"],"partners":["ATG13","FIP200","VCP","TBK1","PXN","KCTD12","PRKCI","TNFRSF14"],"other_free_text":[]},"mechanistic_narrative":"ULK2 is a serine/threonine kinase that functions both as a core initiator of canonical autophagy—redundantly with ULK1 downstream of mTORC1 in response to amino acid deprivation—and as an effector of multiple autophagy-independent signaling pathways including axon guidance, focal adhesion turnover, stress granule disassembly, and innate immune activation [PMID:21460635, PMID:29099309, PMID:38163960, PMID:30979586, PMID:34560002]. ULK2 autophosphorylates in its proline/serine-rich domain and operates within an ATG13–FIP200–AMPK complex; PKA-mediated phosphorylation at Ser1027 drives its Kapβ2-dependent nuclear import and attenuates autophagic activity, while PKCλ/ι phosphorylation targets ULK2 for endosomal microautophagic degradation [PMID:10557072, PMID:26052940, PMID:34560002, PMID:16]. ULK2 directly phosphorylates substrates including VCP/p97 (enhancing stress granule clearance), paxillin (inhibiting focal adhesion assembly and cell migration), TBK1 (activating STING-mediated interferon signaling), CARMA2sh (suppressing NF-κB), and c-Jun (suppressing glycolysis), and is uniquely required in skeletal muscle for selective autophagy of ubiquitinated protein aggregates [PMID:30979586, PMID:38163960, PMID:34560002, PMID:28230860, PMID:41719166, PMID:31361156]. In neurons, ULK2 deficiency causes p62 accumulation that sequesters GABARAP-family proteins and reduces GABAA receptor surface expression, producing excitatory–inhibitory imbalance [PMID:29893844]."},"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 all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ULK2"},"hgnc":{"alias_symbol":["KIAA0623","Unc51.2","ATG1B"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYT8","domains":[{"cath_id":"3.30.200.20","chopping":"2-50_62-88","consensus_level":"medium","plddt":88.9746,"start":2,"end":88},{"cath_id":"1.10.510.10","chopping":"89-273","consensus_level":"high","plddt":91.3905,"start":89,"end":273},{"cath_id":"-","chopping":"821-849_878-1034","consensus_level":"medium","plddt":85.9745,"start":821,"end":1034}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYT8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYT8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYT8-F1-predicted_aligned_error_v6.png","plddt_mean":58.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ULK2","jax_strain_url":"https://www.jax.org/strain/search?query=ULK2"},"sequence":{"accession":"Q8IYT8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYT8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYT8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYT8"}},"corpus_meta":[{"pmid":"21690395","id":"PMC_21690395","title":"Ammonia-induced 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Domain chimera analysis with C. elegans UNC-51 showed that kinase and PS domain functions are conserved across species, while the C-terminal domain acts in a species-specific manner.\",\n      \"method\": \"In vitro autophosphorylation assay with truncation mutants; ULK2/UNC-51 chimeric kinase rescue experiments in C. elegans\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis/truncation analysis and chimeric rescue experiments\",\n      \"pmids\": [\"10557072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ULK1 and ULK2 are functionally redundant kinases required for autophagy in response to amino acid (nitrogen) deprivation in fibroblasts, but not for autophagy induced by glucose deprivation or ammonia. In cerebellar granule neurons, ULK1 but not ULK2 is required for the autophagic response to low potassium, demonstrating cell-type-specific redundancy.\",\n      \"method\": \"Double knockout MEFs (Ulk1/2-/-) and single knockout analysis; autophagy assays under nutrient deprivation; genetic epistasis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double KO with defined cellular phenotype, replicated across two papers (PMID 21460635, 21690395)\",\n      \"pmids\": [\"21460635\", \"21690395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Atg13 and FIP200 form a complex with ULK1/2, but Atg13 has autophagy-inducing functions independent of ULK1/2 kinase activity; simultaneous knockout of Ulk1 and Ulk2 did not fully recapitulate the autophagy defect of Atg13 loss, indicating Atg13 acts upstream in a ULK1/2-independent manner as well.\",\n      \"method\": \"Atg13-deficient cells combined with Ulk1/Ulk2 double knockout; autophagy induction assays; identification of Ulk1-dependent phosphorylation sites on Atg13\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with multiple KO lines and phosphosite mapping\",\n      \"pmids\": [\"22024743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In zebrafish, Ulk2 promotes neuropil elaboration in habenular neurons. Kctd12.1 was identified as a novel binding partner of Ulk2 (via protein interaction screen) that asymmetrically inhibits Ulk2 activity, causing left-right differences in habenular neuropil formation. Knockdown of Ulk2 reduces neuropil elaboration; overexpression causes excess elaboration.\",\n      \"method\": \"Screen for Kctd12.1-interacting proteins uncovering Ulk2 interaction; morpholino knockdown and overexpression in zebrafish; genetic mutation of kctd12\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — protein interaction plus loss- and gain-of-function in zebrafish ortholog, single lab\",\n      \"pmids\": [\"21734278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In 3T3-L1 adipocytes, ULK2 knockdown reduces basal autophagy and mitochondrial respiration, and has opposing effects on fatty acid oxidation and uptake compared to ULK1, demonstrating distinct (non-redundant) roles of ULK1 and ULK2 in lipid metabolism.\",\n      \"method\": \"shRNA knockdown of Ulk1 and Ulk2 in differentiated adipocytes; lipolysis assays, fatty acid oxidation/uptake, mitochondrial respiration measurements\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple metabolic readouts, single lab\",\n      \"pmids\": [\"24135897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ULK2 overexpression induces autophagy and inhibits glioma cell growth; a kinase-dead mutant of ULK2 fails to induce autophagy and fails to inhibit growth. Growth inhibition requires the autophagy-inducing activity of ULK2 (demonstrated in ATG5+/+ but not ATG5-/- cells).\",\n      \"method\": \"Ectopic overexpression of wild-type vs. kinase mutant ULK2; autophagy assays; ATG5-/- cells; in vivo tumor growth\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — active-site mutagenesis combined with ATG5 genetic epistasis and in vivo validation\",\n      \"pmids\": [\"24923441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ULK2 is transported to the nucleus via karyopherin beta 2 (Kapβ2) through a PY-NLS motif ((774)GPGFGSSPPGAEAAPSLRYVPY(795)) in its S/P domain. PKA phosphorylates ULK2 at Ser1027, which promotes dissociation from Atg13 and FIP200, nuclear localization, and reduced autophagic activity. The cytoplasmic-localization mutant (P794A) shows increased autophagy.\",\n      \"method\": \"Pull-down assay (in vitro and in vivo); confocal microscopy co-localization; mutagenesis of PY-NLS (P794A) and Ser1027; transient transfection autophagy assays; in vitro kinase assay\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis, pull-down, co-localization, functional assays showing phosphorylation-dependent nuclear translocation and autophagy regulation\",\n      \"pmids\": [\"26052940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In zebrafish, Ulk2 positively regulates dendrite branching and elaboration in habenular neurons via interaction with Kctd12 proteins through a proline-serine-rich domain. Loss of Kctd12 results in increased dendritogenesis and decreased anxiety behavior, establishing a Kctd12–Ulk2 regulatory axis in neural circuit development.\",\n      \"method\": \"Genetic loss-of-function (ulk2 morpholino, kctd12 mutants) and gain-of-function in zebrafish; behavioral assays; domain mapping of Ulk2–Kctd12 interaction\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis and domain mapping in zebrafish ortholog, single lab\",\n      \"pmids\": [\"25329151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ULK1 and ULK2 regulate axon guidance and defasciculation in the developing mouse forebrain via an autophagy-independent mechanism. CNS-specific double knockout mice show corpus callosum, anterior commissure, and thalamocortical axon defects not observed in Atg7 or Rb1cc1 single-KO mice, placing ULK1/2 in a noncanonical pathway for axon guidance.\",\n      \"method\": \"CNS-specific conditional double-knockout mice (Nes-Cre); comparison with Atg7-/- and Rb1cc1-/- mice; neuroanatomical analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with genetic epistasis against autophagy-null mice, strong phenotypic evidence for autophagy-independent pathway\",\n      \"pmids\": [\"29099309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ULK2 binds to and phosphorylates CARMA2sh, inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10 in human keratinocytes. Psoriasis-associated missense mutants of CARMA2sh escape ULK2-mediated phosphorylation and inhibition.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assays; lysosomal degradation assays; NF-κB reporter assays; mutant CARMA2sh analysis in keratinocytes\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding and phosphorylation assays with disease-linked mutants, single lab\",\n      \"pmids\": [\"28230860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ULK2 deficiency in pyramidal neurons leads to p62 accumulation and selective reduction of GABAA receptor surface expression, causing excitatory-inhibitory imbalance in the prefrontal cortex. Reducing p62 levels or blocking p62-GABARAPL2 (GABARAP-associated protein) interaction restored GABAA receptor surface expression and behavioral deficits.\",\n      \"method\": \"Ulk2 heterozygous mouse model; biochemical fractionation; immunofluorescence; behavioral assays; peptide interference with p62-GABARAPL2 interaction; genetic p62 dosage reduction\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO model with multiple orthogonal rescue approaches establishing mechanistic pathway\",\n      \"pmids\": [\"29893844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ULK1 and ULK2 localize to stress granules and phosphorylate VCP/p97, increasing VCP's ATPase activity and its ability to disassemble stress granules. Loss of ULK1/2 in mice causes vacuolar myopathy with ubiquitin and TDP-43-positive inclusions resembling IBM caused by VCP mutations.\",\n      \"method\": \"Co-localization by imaging; in vitro phosphorylation assay of VCP by ULK1/2; VCP ATPase activity assay; Ulk1/2-/- mouse model with myopathy characterization; ULK1/2 agonist treatment\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro phosphorylation assay of VCP, enzymatic activity assay, in vivo KO model, and pharmacological validation\",\n      \"pmids\": [\"30979586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ULK2 (but not ULK1) is highly enriched in skeletal muscle and is uniquely required for basal selective autophagy of insoluble ubiquitinated protein aggregates associated with p62/SQSTM1 and NBR1. ULK2 deficiency causes myofiber atrophy, degeneration, and impaired muscle force without globally impairing autophagosome formation or lysosomal function.\",\n      \"method\": \"Skeletal muscle-specific Ulk2 KO mice compared to Ulk1 KO; ubiquitinated protein aggregate accumulation assays; p62/NBR1 co-localization; muscle force measurements; autophagy flux assays\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple orthogonal readouts, comparison to ULK1 KO establishing specificity\",\n      \"pmids\": [\"31361156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKCλ/ι directly phosphorylates and represses ULK2, promoting its degradation via endosomal microautophagy through a ubiquitin-dependent mechanism. Loss of PKCλ/ι increases enzymatically active ULK2, which directly phosphorylates and activates TBK1 to stimulate STING-mediated interferon signaling and enhance anti-tumor CD8+ T cell recruitment.\",\n      \"method\": \"In vitro kinase assay (PKCλ/ι phosphorylating ULK2); co-immunoprecipitation; ULK2 in vitro phosphorylation of TBK1; endosomal microautophagy degradation assays; PKCλ/ι-KO mouse intestinal tumor model; single-cell multiplex imaging\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assays for both PKCλ/ι→ULK2 and ULK2→TBK1, mechanistic degradation studies, in vivo tumor model validation\",\n      \"pmids\": [\"34560002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Perinatal loss of both ULK1 and ULK2 in cardiomyocytes impairs autophagy and causes age-related cardiomyopathy; perinatal loss of either alone enhances basal autophagy via compensatory upregulation of the remaining paralog. Adult-specific loss of ULK1 (but not ULK2) causes rapidly developing cardiomyopathy and heart failure with mitochondrial defects, indicating developmental-stage-specific functional differentiation.\",\n      \"method\": \"Cardiomyocyte-specific conditional KO mice (perinatal and inducible adult); autophagy flux assays; mitochondrial respiration; cardiac function measurements; trehalose rescue\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple conditional KO models with orthogonal functional and biochemical readouts\",\n      \"pmids\": [\"35104184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ULK1 and ULK2 inhibit focal adhesion assembly and F-actin formation by phosphorylating the adhesion protein paxillin (PXN), preventing breast cancer cell migration in an autophagy-independent manner. ULK1/2-mediated serine phosphorylation of PXN counteracts PTK2 (FAK) and SRC-mediated tyrosine phosphorylation at adjacent residues, gatekeeping mechanotransduction.\",\n      \"method\": \"In vitro phosphorylation assay of PXN; mutational analysis of PXN phosphosites; focal adhesion assembly imaging; F-actin quantification; cell migration assays with ULK1/2 KO/KD\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro phosphorylation assay with mutagenesis plus functional migration/adhesion readouts in autophagy-independent context\",\n      \"pmids\": [\"38163960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ULK2 forms a stable complex with FIP200, which interacts specifically with AMPK α1 and γ1 subunits (identified by mass spectrometry). ShRNA-mediated knockdown of ULK2 in CML cells induces AMPK activation, promotes cytoplasmic accumulation of ULK1 and FIP200, and triggers autophagy-dependent degradation of BCR::ABL, leading to cell death.\",\n      \"method\": \"Mass spectrometry interactome analysis; co-immunoprecipitation; shRNA knockdown of ULK2 in 293FT and CML cells; autophagy flux and BCR::ABL degradation assays\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — MS-based complex identification plus KD with functional readouts, single lab\",\n      \"pmids\": [\"40664084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated N6-methyladenosine (m6A) modification upregulates ULK2 mRNA expression in hypertrophic scar fibroblasts, promoting autophagy and fibroblast-to-myofibroblast differentiation; silencing METTL3 impairs ULK2-driven autophagic flux and reduces scar formation in vivo.\",\n      \"method\": \"MeRIP-seq (m6A RNA immunoprecipitation sequencing); qRT-PCR; Western blotting; METTL3 siRNA knockdown; transmission electron microscopy; rabbit ear scar model\",\n      \"journal\": \"International Journal of Biological Macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP-seq identifies m6A modification site on ULK2 with functional KD validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"40409645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ULK2 overexpression in cisplatin-resistant ovarian cancer organoids suppresses glycolysis and restores chemosensitivity. Phosphoproteomics revealed ULK2 phosphorylates c-Jun at Ser243, promoting c-Jun degradation and reducing glycolytic gene expression; c-Jun overexpression counteracts ULK2-induced chemosensitivity and glycolysis suppression.\",\n      \"method\": \"Phosphoproteomics in ULK2-overexpressing organoids; CCK-8 and in vivo experiments; glycolysis assays; c-Jun overexpression rescue\",\n      \"journal\": \"Science Progress\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphoproteomics-identified substrate with functional rescue experiment, single lab, novel substrate\",\n      \"pmids\": [\"41719166\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ULK2 is a serine/threonine kinase (with autophosphorylation in its PS domain) that, redundantly with ULK1, initiates canonical autophagy downstream of mTORC1 in response to amino acid deprivation by operating within an ATG13/FIP200/AMPK complex, while also performing autophagy-independent functions including phosphorylation of VCP/p97 to disassemble stress granules, phosphorylation of paxillin (PXN) to inhibit focal adhesion assembly and cell migration, phosphorylation of TBK1 to activate STING-mediated interferon signaling (itself regulated by PKCλ/ι-mediated phosphorylation and microautophagic degradation), phosphorylation of CARMA2sh to suppress NF-κB, phosphorylation of c-Jun to suppress glycolysis, regulation of GABAA receptor surface expression via autophagy-dependent p62 clearance, and promotion of axon guidance and dendritogenesis through noncanonical pathways, with its nuclear vs. cytoplasmic localization governed by PKA-mediated Ser1027 phosphorylation and Kapβ2-dependent nuclear import.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ULK2 is a serine/threonine kinase that functions both as a core initiator of canonical autophagy—redundantly with ULK1 downstream of mTORC1 in response to amino acid deprivation—and as an effector of multiple autophagy-independent signaling pathways including axon guidance, focal adhesion turnover, stress granule disassembly, and innate immune activation [PMID:21460635, PMID:29099309, PMID:38163960, PMID:30979586, PMID:34560002]. ULK2 autophosphorylates in its proline/serine-rich domain and operates within an ATG13–FIP200–AMPK complex; PKA-mediated phosphorylation at Ser1027 drives its Kapβ2-dependent nuclear import and attenuates autophagic activity, while PKCλ/ι phosphorylation targets ULK2 for endosomal microautophagic degradation [PMID:10557072, PMID:26052940, PMID:34560002, PMID:16]. ULK2 directly phosphorylates substrates including VCP/p97 (enhancing stress granule clearance), paxillin (inhibiting focal adhesion assembly and cell migration), TBK1 (activating STING-mediated interferon signaling), CARMA2sh (suppressing NF-κB), and c-Jun (suppressing glycolysis), and is uniquely required in skeletal muscle for selective autophagy of ubiquitinated protein aggregates [PMID:30979586, PMID:38163960, PMID:34560002, PMID:28230860, PMID:41719166, PMID:31361156]. In neurons, ULK2 deficiency causes p62 accumulation that sequesters GABARAP-family proteins and reduces GABAA receptor surface expression, producing excitatory–inhibitory imbalance [PMID:29893844].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that ULK2 possesses intrinsic serine/threonine kinase activity with autophosphorylation in its PS domain, and that kinase/PS domain functions are evolutionarily conserved with C. elegans UNC-51, provided the foundational biochemical identity of ULK2 as an active kinase.\",\n      \"evidence\": \"In vitro autophosphorylation assays with truncation mutants and ULK2/UNC-51 chimeric rescue in C. elegans\",\n      \"pmids\": [\"10557072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mammalian in vivo substrates identified\", \"Kinase regulation mechanisms unknown\", \"Physiological role in mammalian cells untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that ULK1 and ULK2 are functionally redundant for amino-acid-deprivation-induced autophagy but dispensable for glucose/ammonia-induced autophagy, and that they function within an ATG13–FIP200 complex with ATG13 retaining ULK-independent activity, defined the scope and limits of ULK2's canonical autophagy role.\",\n      \"evidence\": \"Ulk1/Ulk2 double-knockout MEFs; Atg13-deficient cells; multiple autophagy induction conditions\",\n      \"pmids\": [\"21460635\", \"21690395\", \"22024743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of stimulus-specific autophagy pathway selectivity unknown\", \"Relative contribution of ULK2 kinase activity vs. scaffolding unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of Kctd12.1 as a ULK2-binding partner that asymmetrically inhibits ULK2 to generate left–right differences in habenular neuropil elaboration revealed a neurodevelopmental function for ULK2 beyond autophagy.\",\n      \"evidence\": \"Protein interaction screen and morpholino knockdown/overexpression in zebrafish\",\n      \"pmids\": [\"21734278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Kctd12 inhibits ULK2 kinase activity uncharacterized\", \"Not confirmed in mammalian neurons at this stage\", \"Direct phosphorylation substrate in this context unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that ULK2's kinase activity is required for autophagy-dependent tumor growth inhibition in glioma (via ATG5 epistasis) established that ULK2 can function as a tumor suppressor through its autophagy-initiating activity.\",\n      \"evidence\": \"Kinase-dead ULK2 mutant; ATG5-null epistasis; in vivo tumor growth assays\",\n      \"pmids\": [\"24923441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream targets mediating growth suppression not identified\", \"Whether this is ULK2-specific or shared with ULK1 not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that PKA phosphorylates ULK2 at Ser1027, causing dissociation from ATG13/FIP200 and Kapβ2-dependent nuclear import, revealed a phosphorylation switch governing ULK2 subcellular distribution and autophagy activity.\",\n      \"evidence\": \"Pull-down, confocal imaging, PY-NLS and Ser1027 mutagenesis, in vitro kinase assay\",\n      \"pmids\": [\"26052940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear function of ULK2 unknown\", \"Physiological stimuli that activate PKA-mediated nuclear import uncharacterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CNS-specific Ulk1/Ulk2 double knockout in mice produced corpus callosum and axon guidance defects not seen in canonical autophagy knockouts (Atg7, Rb1cc1), establishing a bona fide autophagy-independent neurodevelopmental function for ULK1/2.\",\n      \"evidence\": \"Nestin-Cre conditional double KO mice compared with Atg7−/− and Rb1cc1−/− mice; neuroanatomical analysis\",\n      \"pmids\": [\"29099309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of ULK1/2 in axon guidance unidentified\", \"Individual contributions of ULK1 vs. ULK2 to axon guidance not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of CARMA2sh as a direct ULK2 phosphorylation substrate that, when phosphorylated, promotes BCL10 lysosomal degradation and NF-κB suppression—with psoriasis-associated CARMA2sh mutants escaping this regulation—linked ULK2 to skin inflammatory disease mechanisms.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, NF-κB reporter assays, disease-associated mutant analysis in keratinocytes\",\n      \"pmids\": [\"28230860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylation sites on CARMA2sh not mapped\", \"Not independently replicated\", \"In vivo relevance in psoriasis models untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that ULK2 haploinsufficiency causes p62 accumulation that sequesters GABARAPL2 and reduces GABAA receptor surface levels in prefrontal cortex neurons, correctable by p62 reduction, established a specific mechanism linking ULK2 to excitatory–inhibitory balance.\",\n      \"evidence\": \"Ulk2 heterozygous mice; biochemical fractionation; peptide interference with p62–GABARAPL2; genetic p62 dosage reduction; behavioral assays\",\n      \"pmids\": [\"29893844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether full ULK2 KO worsens the phenotype not shown\", \"How p62–GABARAPL2 interaction specifically affects GABAA trafficking not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies revealed non-redundant tissue-specific functions: ULK1/2 phosphorylate VCP/p97 to enhance its ATPase activity and stress granule disassembly (with double-KO mice developing inclusion body myopathy), while ULK2 alone is uniquely required in skeletal muscle for selective autophagy of ubiquitinated protein aggregates.\",\n      \"evidence\": \"In vitro VCP phosphorylation and ATPase assays; Ulk1/2 double-KO myopathy model; skeletal muscle-specific Ulk2 KO with aggregate and force measurements\",\n      \"pmids\": [\"30979586\", \"31361156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific VCP phosphosites mediating stress granule disassembly not fully mapped\", \"Mechanism of ULK2-specific selective autophagy in muscle uncharacterized\", \"Whether ULK2 muscle function is kinase-dependent not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing that PKCλ/ι phosphorylates ULK2 to promote its endosomal microautophagic degradation, and that stabilized ULK2 directly phosphorylates and activates TBK1 to drive STING-mediated interferon signaling and anti-tumor immunity, placed ULK2 at the nexus of autophagy, innate immunity, and tumor microenvironment regulation.\",\n      \"evidence\": \"In vitro kinase assays for PKCλ/ι→ULK2 and ULK2→TBK1; microautophagy degradation assays; PKCλ/ι-KO intestinal tumor model; multiplex imaging\",\n      \"pmids\": [\"34560002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphosites on ULK2 targeted by PKCλ/ι not fully characterized\", \"Whether ULK2→TBK1 axis operates outside intestinal tumors untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Perinatal cardiomyocyte-specific deletion showed compensatory upregulation between ULK1 and ULK2, while adult-specific loss of ULK1 but not ULK2 caused acute cardiomyopathy, demonstrating stage-dependent functional differentiation between the paralogs in the heart.\",\n      \"evidence\": \"Perinatal and inducible adult cardiomyocyte-specific conditional KO mice; autophagy flux; mitochondrial and cardiac function measurements\",\n      \"pmids\": [\"35104184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why adult ULK2 loss is tolerated in heart while ULK1 loss is not remains unexplained at molecular level\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that ULK1/2 phosphorylate paxillin to antagonize FAK/SRC-mediated tyrosine phosphorylation and inhibit focal adhesion assembly revealed an autophagy-independent role in mechanotransduction and cell migration control.\",\n      \"evidence\": \"In vitro PXN phosphorylation; phosphosite mutagenesis; focal adhesion imaging; migration assays with ULK1/2 KO\",\n      \"pmids\": [\"38163960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ULK2 vs. ULK1 to PXN phosphorylation in vivo not resolved\", \"Structural basis of antagonism between serine and tyrosine phosphorylation on PXN unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of ULK2-specific interactions with AMPK α1/γ1 subunits via FIP200, and demonstration that ULK2 knockdown triggers AMPK activation and autophagy-dependent BCR::ABL degradation in CML cells, revealed a ULK2-specific scaffolding role in AMPK regulation with therapeutic implications.\",\n      \"evidence\": \"Mass spectrometry interactome; co-IP; shRNA knockdown in CML cells; autophagy flux and BCR::ABL degradation assays\",\n      \"pmids\": [\"40664084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. FIP200-mediated interaction with AMPK subunits not distinguished\", \"Whether this mechanism operates in primary CML patient cells unknown\", \"Single-lab finding awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Phosphoproteomic identification of c-Jun Ser243 as a direct ULK2 substrate that upon phosphorylation undergoes degradation, suppressing glycolytic gene expression and restoring cisplatin sensitivity in ovarian cancer, expanded ULK2's substrate repertoire to metabolic transcription factors.\",\n      \"evidence\": \"Phosphoproteomics in ULK2-overexpressing organoids; glycolysis assays; c-Jun overexpression rescue; in vivo experiments\",\n      \"pmids\": [\"41719166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro kinase assay directly confirming ULK2 phosphorylation of c-Jun Ser243 not shown\", \"Generalizability beyond cisplatin-resistant ovarian cancer untested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity and function of nuclear ULK2 substrates, the structural basis for substrate selectivity between ULK1 and ULK2, and how ULK2's autophagy-independent functions (axon guidance, focal adhesion regulation, innate immune signaling) are coordinated with its canonical autophagy role in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No nuclear substrates or functions identified despite demonstrated nuclear import\", \"No structural model of ULK2 or ULK2-substrate complexes available\", \"Mechanism of ULK2 specificity in selective muscle autophagy unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 9, 11, 13, 15, 18]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2, 5, 6, 10, 12, 14, 16, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 13, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"ULK2–ATG13–FIP200 complex\"\n    ],\n    \"partners\": [\n      \"ATG13\",\n      \"FIP200\",\n      \"VCP\",\n      \"TBK1\",\n      \"PXN\",\n      \"KCTD12\",\n      \"PRKCI\",\n      \"TNFRSF14\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}