{"gene":"MINK1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2012,"finding":"MINK1 is a component of the STRIPAK (striatin-interacting phosphatase and kinase) complex and directly interacts with STRN4 (Zinedin). STRN4 reduced MINK1 kinase activity in the presence of PP2A catalytic and structural subunits. MINK1 depletion by siRNA caused a cytokinesis defect specifically at the abscission step, revealing an essential role in completing cell division.","method":"Mass spectrometry identification of STRIPAK components, co-immunoprecipitation, siRNA knockdown with time-lapse microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by Co-IP and MS, functional phenotype (abscission failure) with siRNA knockdown, single lab with multiple orthogonal methods","pmids":["22665485"],"is_preprint":false},{"year":2011,"finding":"MINK1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, which is required for localized plasma membrane accumulation of Prickle during β-catenin-independent (Wnt/PCP) signaling. MINK1 was identified as a Prickle-associated protein by mass spectrometry and shown to genetically interact with Prickle during planar cell polarity establishment in Drosophila eye and convergent extension in Xenopus embryos.","method":"Mass spectrometry, co-immunoprecipitation, in vitro kinase assay, genetic interaction in Drosophila and Xenopus, endosomal trafficking assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay demonstrating direct phosphorylation, genetic epistasis in two model organisms, MS identification, multiple orthogonal methods in one study","pmids":["22037766"],"is_preprint":false},{"year":2017,"finding":"MINK1 negatively regulates Th17 cell differentiation by directly phosphorylating SMAD2 at the T324 residue, thereby inhibiting TGF-β-induced SMAD2 activation. Reactive oxygen species (ROS) activate MINK1, which then suppresses SMAD2 phosphorylation and limits Th17 differentiation. MINK1-deficient mice showed enhanced Th17 responses and exacerbated experimental autoimmune encephalomyelitis (EAE).","method":"Direct phosphorylation assay (MINK1 phosphorylating SMAD2 at T324), MINK1 knockout mice, EAE model, ROS treatment assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct phosphorylation of identified residue (T324) demonstrated, in vivo genetic knockout with defined phenotype, ROS-MINK1-SMAD2 axis established with multiple methods","pmids":["28400474"],"is_preprint":false},{"year":2017,"finding":"MAP4K4, MINK1, and TNIK act redundantly as upstream regulators of the DLK/JNK signaling pathway in neurons. These MAP4Ks regulate DLK activation and downstream JNK-dependent phosphorylation of c-Jun in response to trophic factor withdrawal. Pharmacological inhibition of MAP4Ks blocks stabilization and phosphorylation of DLK within axons and subsequent retrograde translocation of the JNK signaling complex to the nucleus. Targeting all three kinases together (but not individually) protects neurons from degeneration.","method":"siRNA knockdown in embryonic DRG neurons, pharmacological inhibition, phosphorylation assays for DLK and c-Jun, axon retrograde signaling assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by genetic knockdown and pharmacological inhibition, defined pathway position (upstream of DLK), multiple orthogonal readouts (DLK phosphorylation, c-Jun phosphorylation, retrograde transport, neuronal survival)","pmids":["28993483"],"is_preprint":false},{"year":2015,"finding":"MINK1 plays an essential role in platelet function, hemostasis, and thrombus formation. MINK1-deficient mice showed prolonged bleeding times, delayed arterial thrombosis, impaired platelet aggregation and secretion, and reduced spreading on fibrinogen. The functional defects were attributed to impaired ADP secretion and associated with reduced ERK, p38, and Akt signaling in platelets.","method":"MINK1 knockout mice, tail-bleeding assay, ferric chloride-induced thrombosis model, microfluidic whole-blood perfusion assay, platelet aggregation and spreading assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple defined in vivo and ex vivo phenotypes, ADP secretion identified as mechanistic basis, signaling pathway components identified","pmids":["26598717"],"is_preprint":false},{"year":2021,"finding":"MINK1 directly phosphorylates NLRP3 at Ser725 (human/mouse), a modification required for priming of NLRP3 inflammasome activation in macrophages. The interaction depends on direct binding between MINK1 and the NLRP3 LRR domain. ROS upregulate MINK1 kinase activity to promote this phosphorylation event. MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis.","method":"In vitro kinase assay (direct phosphorylation of Ser725), co-immunoprecipitation (MINK1-NLRP3 LRR domain interaction), MINK1 knockout mice, sepsis and peritonitis models, ASC oligomerization and caspase activity assays","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct phosphorylation assay identifying specific residue, domain-level interaction mapping, in vivo knockout with multiple phenotypic readouts, ROS-MINK1-NLRP3 axis established","pmids":["34480147"],"is_preprint":false},{"year":2021,"finding":"MINK1 phosphorylates glucocorticoid receptor (GR) at Thr524, which induces binding of 14-3-3 proteins (specifically 14-3-3ζ) to the GR ligand-binding domain. Cell-based approaches confirmed the importance of GR Thr524, GR S617, and MINK1 in inducing GR-14-3-3 binding. MINK1 was identified as the specific kinase for T524 by kinase screen.","method":"Kinase screen, phosphorylated GR peptide binding assays, biophysical studies (SPR/TR-FRET), X-ray crystallography of 14-3-3ζ with phospho-GR peptide, cell-based co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — kinase screen identifying MINK1, X-ray crystal structure of downstream complex, cell-based validation, multiple orthogonal methods in single study","pmids":["33744286"],"is_preprint":false},{"year":2022,"finding":"MINK1 phosphorylates LL5β (PHLDB2), promoting its interaction with CLASP proteins to trigger focal adhesion disassembly. MINK1 enzymatic activity is required for PRICKLE1-LL5β complex assembly and localization, and for cell migration. A phosphoproteomic strategy identified LL5β as a MINK1 substrate alongside PRICKLE1.","method":"Phosphoproteomics (MINK1 substrate identification), kinase inhibitor studies, co-immunoprecipitation, cell migration assays, focal adhesion assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomic substrate identification plus functional validation with kinase inhibitor and protein complex assays, single lab","pmids":["35971817"],"is_preprint":false},{"year":2022,"finding":"MINK1 modulates AKT phosphorylation at Ser473, enabling p-MDM2 (Ser166)-mediated degradation of p53. MINK1 was identified by CRISPR/Cas9 kinome knockout screening as a mediator of 5FU resistance in OSCC. An antibody-based phosphorylation array revealed MINK1 as a negative regulator of p53 through the AKT/MDM2 axis.","method":"CRISPR/Cas9 kinome knockout screen, phosphorylation antibody array, xenograft models (nude mice and zebrafish), western blot for AKT/MDM2/p53 signaling","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide functional screen plus phosphorylation array identifying pathway, in vivo xenograft validation, single lab but multiple readouts","pmids":["36182968"],"is_preprint":false},{"year":2019,"finding":"MINK1 deficiency protects cartilage from degeneration in aging joints through increased SMAD2 phosphorylation (pSMAD2) in chondrocytes, while accelerating OA progress in injury-induced model through enhanced osteogenesis of MSCs in the subchondral bone. Overexpression of MINK1 inhibited SMAD2 phosphorylation in vitro, confirming MINK1 as a negative regulator of TGFβ/SMAD2 signaling.","method":"MINK1 knockout mice (Mink1-/-), aging-related OA and DMM models, in vitro SMAD2 phosphorylation inhibition assay with MINK1 overexpression, immunohistochemistry","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation assay plus in vivo knockout models with defined phenotypes, single lab","pmids":["31647983"],"is_preprint":false},{"year":2004,"finding":"MINK1 protein architecture comprises four domains: an N-terminal kinase domain, a coiled-coil region, a proline-rich region, and a C-terminal GCK domain. Yeast two-hybrid screening identified proteins interacting with the coiled-coil and proline-rich domains of MINK1 that implicate MINK1 in cytoskeletal organization, cell-cycle control, and apoptosis.","method":"Computational fold recognition/threading, yeast two-hybrid screen, gene expression analysis of yeast homologs, homology modeling of kinase domain","journal":"Current medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational prediction with yeast two-hybrid as supporting evidence; no direct biochemical validation of identified interactions","pmids":["15032605"],"is_preprint":false},{"year":2022,"finding":"A de novo balanced translocation disrupting MINK1 between exon 1 and exon 2 (on chromosome 17p13) resulted in >50% reduction in MINK1 expression in patient-derived neural cells. Pathway analysis revealed enrichment of altered neural pathways, implicating MINK1 as a candidate monogenic disease gene for autism, epilepsy, and osteoporosis.","method":"Long-read genome sequencing, optical mapping, transcriptome sequencing of iPSC-derived neuroepithelial stem cells, pathway analysis","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient, loss-of-function by haploinsufficiency with pathway analysis only; no direct mechanistic experiment linking MINK1 to the neural pathways identified","pmids":["36012658"],"is_preprint":false},{"year":2022,"finding":"Mink1 regulates canonical Wnt signaling to define cell fates of the Spemann Organizer and the Left-Right Organizer in Xenopus embryos, required for proper heart development. Unbiased proteomics identified Hmga2 as a downstream target of Mink1; Hmga2 can induce Spemann Organizer cell fates even when β-catenin is depleted, placing it downstream of Mink1 in a β-catenin-independent manner.","method":"Xenopus loss-of-function experiments, unbiased proteomics (Mink1 target identification), rescue experiments with Hmga2, β-catenin depletion","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in Xenopus with defined developmental phenotype, proteomics-based substrate identification, epistasis established between Mink1 and Hmga2, single lab","pmids":["36572140"],"is_preprint":false},{"year":2025,"finding":"Resveratrol reduces cellular miR-17-5p levels, leading to MINK1 upregulation (miR-17-5p directly targets MINK1), which activates the JNK/c-Jun signaling cascade, ultimately upregulating ULBP2 expression on breast cancer cells and enhancing NK cell cytotoxicity. MINK1 knockdown and overexpression experiments in cells confirmed MINK1's role in facilitating JNK and c-Jun activation downstream of miR-17-5p.","method":"Dual-luciferase reporter assay (miR-17-5p targeting MINK1), MINK1 knockdown/overexpression, JNK inhibitor (SP600125), flow cytometry, in vitro and in vivo NK cytotoxicity assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirming direct targeting, knockdown and overexpression with defined signaling readouts (JNK/c-Jun), in vivo validation, single lab","pmids":["39963142"],"is_preprint":false},{"year":2024,"finding":"MINK1 deficiency triggers NF-κB signaling in nucleus pulposus (NP) tissues, leading to increased NP cell pyroptosis and exacerbated intervertebral disc degeneration. In common carp, the MINK1 homolog CcMINK1 interacts with NLRP3 via its S_TKC domain and facilitates NLRP3 phosphorylation, promoting NLRP3 aggregation and activation.","method":"MINK1 knockout mouse models (aging-induced and LSI surgery-induced IVD degeneration), co-immunoprecipitation (CcMINK1-CcNLRP3), overexpression studies, NF-κB pathway analysis","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mammalian data is predominantly phenotypic (KO mice with NF-κB activation); direct mechanistic data (S_TKC domain binding, phosphorylation) is from fish ortholog only","pmids":["38723371"],"is_preprint":false}],"current_model":"MINK1 (MAP4K6) is a Ste20-family serine/threonine kinase that functions as an upstream activator of DLK/JNK signaling in neurons (redundantly with MAP4K4 and TNIK), directly phosphorylates SMAD2 (T324) to suppress Th17 differentiation, phosphorylates NLRP3 (Ser725) to prime inflammasome activation in macrophages, phosphorylates Prickle to regulate its endosomal trafficking in Wnt/PCP signaling, phosphorylates the glucocorticoid receptor (T524) to recruit 14-3-3 proteins, phosphorylates LL5β to facilitate focal adhesion disassembly and cell migration, modulates AKT/MDM2/p53 signaling to influence chemoresistance, and is a component of the STRIPAK complex through direct interaction with STRN4, where PP2A activity within STRIPAK downregulates MINK1 kinase activity and MINK1 itself is required for cytokinesis completion."},"narrative":{"mechanistic_narrative":"MINK1 (MAP4K6) is a Ste20-family serine/threonine kinase that couples upstream signals — frequently reactive oxygen species — to substrate phosphorylation across immune, developmental, cytoskeletal, and cell-division programs [PMID:28400474, PMID:34480147]. In innate immunity it directly phosphorylates NLRP3 at Ser725 through engagement of the NLRP3 LRR domain to prime inflammasome activation in macrophages, with ROS upregulating MINK1 activity, such that MINK1 loss blunts inflammatory responses in sepsis and peritonitis [PMID:34480147]. In adaptive immunity ROS-activated MINK1 phosphorylates SMAD2 at Thr324 to inhibit TGF-β-induced SMAD2 activation and restrain Th17 differentiation, with MINK1-deficient mice showing exacerbated autoimmune encephalomyelitis [PMID:28400474]; this same negative regulation of SMAD2 phosphorylation operates in chondrocytes [PMID:31647983]. MINK1 also acts redundantly with MAP4K4 and TNIK as an upstream activator of DLK/JNK signaling in neurons, controlling DLK stabilization, c-Jun phosphorylation, and retrograde injury signaling [PMID:28993483]. In Wnt/planar cell polarity signaling it phosphorylates Prickle on a conserved threonine to direct Rab5-dependent endosomal trafficking and membrane accumulation [PMID:22037766], and through phosphorylation of LL5β (PHLDB2) it promotes CLASP recruitment, PRICKLE1–LL5β complex assembly, focal adhesion disassembly, and cell migration [PMID:35971817]. MINK1 phosphorylates the glucocorticoid receptor at Thr524 to recruit 14-3-3ζ to its ligand-binding domain [PMID:33744286], and it is a STRIPAK-complex component that binds STRN4 — whose associated PP2A downregulates MINK1 kinase activity — with MINK1 being required to complete cytokinesis at abscission [PMID:22665485]. A de novo balanced translocation reducing MINK1 expression has been described as a candidate monogenic basis for autism, epilepsy, and osteoporosis [PMID:36012658].","teleology":[{"year":2004,"claim":"Before functional characterization, the question was what protein architecture and interaction surfaces MINK1 presents; domain dissection defined a kinase domain, coiled-coil, proline-rich region, and GCK domain with interactors implicating cytoskeleton, cell cycle, and apoptosis.","evidence":"Computational fold recognition and yeast two-hybrid screening of coiled-coil and proline-rich domains","pmids":["15032605"],"confidence":"Low","gaps":["Interactions predicted but not biochemically validated","No catalytic substrate identified","Functional roles inferred only from interactor identity"]},{"year":2011,"claim":"Establishing MINK1 as a direct kinase in a defined pathway, it was shown to phosphorylate Prickle on a conserved threonine to govern Rab5-dependent endosomal trafficking in Wnt/PCP signaling.","evidence":"Mass spectrometry, in vitro kinase assay, and genetic interaction in Drosophila and Xenopus","pmids":["22037766"],"confidence":"High","gaps":["Phosphosite residue not mapped to a specific number","Mechanism linking phosphorylation to trafficking incomplete","Mammalian PCP relevance not addressed"]},{"year":2012,"claim":"To place MINK1 in a regulatory complex and the cell cycle, it was identified as a STRIPAK subunit bound to STRN4 whose PP2A activity suppresses MINK1, and required for abscission-stage cytokinesis.","evidence":"STRIPAK mass spectrometry, co-immunoprecipitation, and siRNA with time-lapse microscopy","pmids":["22665485"],"confidence":"High","gaps":["Cytokinesis substrate of MINK1 not identified","Mechanism of PP2A-mediated MINK1 inactivation unresolved"]},{"year":2015,"claim":"Addressing MINK1 in vivo physiology, knockout mice revealed an essential role in platelet function, hemostasis, and thrombosis tied to impaired ADP secretion and reduced ERK/p38/Akt signaling.","evidence":"Knockout mice with bleeding, thrombosis, aggregation, and spreading assays","pmids":["26598717"],"confidence":"High","gaps":["Direct platelet substrate of MINK1 not defined","Connection between MINK1 and the ERK/p38/Akt readouts mechanistically unmapped"]},{"year":2017,"claim":"Two studies defined MINK1 as a ROS-responsive negative regulator of immunity, directly phosphorylating SMAD2 at Thr324 to limit Th17 differentiation, and as a redundant upstream activator of neuronal DLK/JNK signaling.","evidence":"Direct phosphorylation assays, knockout mice, EAE model, and DRG neuron knockdown/inhibition with DLK and c-Jun readouts","pmids":["28400474","28993483"],"confidence":"High","gaps":["Mechanism of ROS sensing by MINK1 not resolved","Redundancy with MAP4K4/TNIK obscures individual neuronal contribution","Direct DLK substrate relationship not established"]},{"year":2021,"claim":"MINK1 was shown to phosphorylate NLRP3 at Ser725 via the LRR domain to prime inflammasome activation, and to phosphorylate the glucocorticoid receptor at Thr524 to recruit 14-3-3ζ, broadening its direct-substrate repertoire.","evidence":"In vitro kinase assays, domain-mapped co-IP, knockout sepsis/peritonitis models, kinase screen, and X-ray crystallography of 14-3-3ζ with phospho-GR peptide","pmids":["34480147","33744286"],"confidence":"High","gaps":["Upstream activation of MINK1 in macrophages partially defined (ROS) but signaling input unclear","Functional consequence of GR Thr524 phosphorylation on transcription not fully characterized"]},{"year":2022,"claim":"Expanding MINK1's cytoskeletal and oncogenic roles, it was found to phosphorylate LL5β to drive focal adhesion disassembly and migration, to suppress p53 via AKT/MDM2 conferring chemoresistance, and to regulate canonical Wnt fate decisions through the downstream target Hmga2.","evidence":"Phosphoproteomics, kinase-inhibitor and migration assays, CRISPR kinome screen with phospho-array and xenografts, and Xenopus loss-of-function with proteomics and Hmga2 rescue","pmids":["35971817","36182968","36572140"],"confidence":"Medium","gaps":["Whether MINK1 directly phosphorylates AKT pathway components or acts indirectly is unresolved","Hmga2 regulation mechanism downstream of MINK1 not defined","Single-lab findings per role"]},{"year":2022,"claim":"A candidate human disease link emerged from a de novo translocation reducing MINK1 expression, implicating haploinsufficiency in autism, epilepsy, and osteoporosis.","evidence":"Long-read genome sequencing, optical mapping, and transcriptomics of patient iPSC-derived neuroepithelial cells","pmids":["36012658"],"confidence":"Low","gaps":["Single patient with pathway analysis only","No mechanistic experiment linking MINK1 loss to the neural phenotypes","Causality versus correlation not established"]},{"year":2024,"claim":"MINK1's inflammasome and degenerative roles were extended to intervertebral disc degeneration, where deficiency triggers NF-κB-driven NP cell pyroptosis, with direct NLRP3-domain interaction shown only in a fish ortholog.","evidence":"Knockout mouse IVD degeneration models with NF-κB analysis and CcMINK1–CcNLRP3 co-IP in common carp","pmids":["38723371"],"confidence":"Low","gaps":["Mammalian direct NLRP3 interaction not demonstrated here","Mechanistic data restricted to fish ortholog","Phenotypic mammalian data only"]},{"year":2025,"claim":"A regulatory axis upstream of MINK1 was defined in which miR-17-5p directly targets MINK1, and MINK1 activates JNK/c-Jun to upregulate ULBP2 and enhance NK cytotoxicity against breast cancer cells.","evidence":"Dual-luciferase reporter, MINK1 knockdown/overexpression with JNK inhibition, flow cytometry, and in vivo NK cytotoxicity","pmids":["39963142"],"confidence":"Medium","gaps":["Direct MINK1 substrate in JNK activation not identified","Generalizability beyond breast cancer context unknown"]},{"year":null,"claim":"How MINK1 substrate selection is governed across its diverse contexts — and how a single ROS-activated kinase is partitioned between inflammasome priming, SMAD2 inhibition, DLK/JNK activation, PCP trafficking, and cytokinesis — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model of context-specific substrate targeting","STRIPAK/PP2A regulation not integrated with the various effector pathways","Direct human disease causation unconfirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5,6,7]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,9,12]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[4]}],"complexes":["STRIPAK"],"partners":["STRN4","NLRP3","SMAD2","PRICKLE1","PHLDB2","NR3C1","YWHAZ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N4C8","full_name":"Misshapen-like kinase 1","aliases":["GCK family kinase MiNK","MAPK/ERK kinase kinase kinase 6","MEK kinase kinase 6","MEKKK 6","Misshapen/NIK-related kinase","Mitogen-activated protein kinase kinase kinase kinase 6"],"length_aa":1332,"mass_kda":149.8,"function":"Serine/threonine kinase which acts as a negative regulator of Ras-related Rap2-mediated signal transduction to control neuronal structure and AMPA receptor trafficking (PubMed:10708748, PubMed:16337592). Required for normal synaptic density, dendrite complexity, as well as surface AMPA receptor expression in hippocampal neurons (By similarity). Can activate the JNK and MAPK14/p38 pathways and mediates stimulation of the stress-activated protein kinase MAPK14/p38 MAPK downstream of the Raf/ERK pathway. Phosphorylates TANC1 upon stimulation by RAP2A, MBP and SMAD1 (PubMed:18930710, PubMed:21690388). Has an essential function in negative selection of thymocytes, perhaps by coupling NCK1 to activation of JNK1 (By similarity). Activator of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. MAP4Ks act in parallel to and are partially redundant with STK3/MST2 and STK4/MST2 in the phosphorylation and activation of LATS1/2, and establish MAP4Ks as components of the expanded Hippo pathway (PubMed:26437443) Isoform 4 can activate the JNK pathway. Involved in the regulation of actin cytoskeleton reorganization, cell-matrix adhesion, cell-cell adhesion and cell migration","subcellular_location":"Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q8N4C8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MINK1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000141503","cell_line_id":"CID001221","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cell_contact","grade":2},{"compartment":"big_aggregates","grade":1}],"interactors":[{"gene":"ALKBH5","stoichiometry":4.0},{"gene":"NFYA","stoichiometry":4.0},{"gene":"ERCC6L","stoichiometry":0.2},{"gene":"PRKAB1","stoichiometry":0.2},{"gene":"PKNOX1;PKNOX2","stoichiometry":0.2},{"gene":"FECH","stoichiometry":0.2},{"gene":"SUB1","stoichiometry":0.2},{"gene":"STK26","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001221","total_profiled":1310},"omim":[{"mim_id":"616023","title":"SR-RELATED C-TERMINAL DOMAIN-ASSOCIATED FACTOR 4; SCAF4","url":"https://www.omim.org/entry/616023"},{"mim_id":"609426","title":"MISSHAPEN/NIK-RELATED KINASE 1; MINK1","url":"https://www.omim.org/entry/609426"},{"mim_id":"301016","title":"RAS-RELATED PROTEIN 2C; RAP2C","url":"https://www.omim.org/entry/301016"},{"mim_id":"179541","title":"RAS-RELATED PROTEIN 2B; RAP2B","url":"https://www.omim.org/entry/179541"},{"mim_id":"179540","title":"RAS-RELATED PROTEIN 2A; RAP2A","url":"https://www.omim.org/entry/179540"}],"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/MINK1"},"hgnc":{"alias_symbol":["B55","MINK","ZC3","MAP4K6","YSK2"],"prev_symbol":[]},"alphafold":{"accession":"Q8N4C8","domains":[{"cath_id":"3.30.200.20","chopping":"11-108","consensus_level":"medium","plddt":84.9196,"start":11,"end":108},{"cath_id":"1.10.510.10","chopping":"110-312","consensus_level":"medium","plddt":86.4052,"start":110,"end":312},{"cath_id":"2.130.10.10","chopping":"1011-1025_1111-1324","consensus_level":"medium","plddt":88.7277,"start":1011,"end":1324}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4C8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4C8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4C8-F1-predicted_aligned_error_v6.png","plddt_mean":63.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MINK1","jax_strain_url":"https://www.jax.org/strain/search?query=MINK1"},"sequence":{"accession":"Q8N4C8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N4C8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N4C8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4C8"}},"corpus_meta":[{"pmid":"18922469","id":"PMC_18922469","title":"Structure 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/41407311","citation_count":0,"is_preprint":false},{"pmid":"41928937","id":"PMC_41928937","title":"FAM122A inhibition of PP2A-B55 through a bipartite binding mechanism.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41928937","citation_count":0,"is_preprint":false},{"pmid":"41967399","id":"PMC_41967399","title":"Generative deep learning-driven de novo design of targeted MAP4K6 inhibitors.","date":"2026","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41967399","citation_count":0,"is_preprint":false},{"pmid":"38302392","id":"PMC_38302392","title":"The yin and yang of nuclear envelope breakdown through the activity of phosphatase holoenzyme PP2A-B55SUR-6.","date":"2024","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38302392","citation_count":0,"is_preprint":false},{"pmid":"42129183","id":"PMC_42129183","title":"Greatwall depletion from Xenopus oocytes reveals a key role of the cyclin B/CDK1-PP2A-B55 balance in the coordination of meiotic events.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42129183","citation_count":0,"is_preprint":false},{"pmid":"8302299","id":"PMC_8302299","title":"Generation of HLA-B55 restricted T lymphocyte mediated cytotoxicity against autologous LCL.","date":"1994","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8302299","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.21.639482","title":"Phosphatase specificity influences phosphorylation timing of CDK substrates during the cell cycle","date":"2025-02-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.21.639482","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.08.674995","title":"Reconstitution of phospho-regulated mitotic chromatid assembly and disassembly","date":"2025-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.674995","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.08.652831","title":"SF3B1  <sup>K700E</sup>  rewires splicing of cell-cycle regulators","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.08.652831","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41546,"output_tokens":4916,"usd":0.099189,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12520,"output_tokens":4113,"usd":0.082712,"stage2_stop_reason":"end_turn"},"total_usd":0.181901,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to carefully distinguish between:\n1. Papers about MINK1 (MAP4K6, the Ste20-family kinase)\n2. Papers about PP2A-B55 (a regulatory subunit of PP2A, unrelated to MINK1)\n3. Papers about \"B55\" as a bacterial strain, peptide, adenovirus type, or other alias collisions\n\nThe query gene is **MINK1** (also known as MAP4K6, YSK2, ZC3). The alias \"B55\" in the HGNC list is presumably a historical alias for MINK1, but the vast majority of papers in this corpus are about PP2A-B55 (the phosphatase regulatory subunit), which is a completely different protein. I should NOT extract discoveries about PP2A-B55 as if they were about MINK1.\n\nPapers clearly about MINK1 (MAP4K6): [8, 11, 13, 18, 23, 28, 43, 44, 47, 54, 55, 60, 61, 64, 65, 78]\n\nLet me also check [32] - it mentions MINK1/JNK pathway but as a ceRNA/lncRNA study - it does describe MINK1 activating JNK. Paper [48] mentions MINK1 regulation of Th17. Paper [44] discusses MINK1 and TGFβ/SMAD2.\n\nNow extracting mechanistic discoveries from MINK1-specific papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"MINK1 is a component of the STRIPAK (striatin-interacting phosphatase and kinase) complex and directly interacts with STRN4 (Zinedin). STRN4 reduced MINK1 kinase activity in the presence of PP2A catalytic and structural subunits. MINK1 depletion by siRNA caused a cytokinesis defect specifically at the abscission step, revealing an essential role in completing cell division.\",\n      \"method\": \"Mass spectrometry identification of STRIPAK components, co-immunoprecipitation, siRNA knockdown with time-lapse microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by Co-IP and MS, functional phenotype (abscission failure) with siRNA knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22665485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MINK1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, which is required for localized plasma membrane accumulation of Prickle during β-catenin-independent (Wnt/PCP) signaling. MINK1 was identified as a Prickle-associated protein by mass spectrometry and shown to genetically interact with Prickle during planar cell polarity establishment in Drosophila eye and convergent extension in Xenopus embryos.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, in vitro kinase assay, genetic interaction in Drosophila and Xenopus, endosomal trafficking assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay demonstrating direct phosphorylation, genetic epistasis in two model organisms, MS identification, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22037766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MINK1 negatively regulates Th17 cell differentiation by directly phosphorylating SMAD2 at the T324 residue, thereby inhibiting TGF-β-induced SMAD2 activation. Reactive oxygen species (ROS) activate MINK1, which then suppresses SMAD2 phosphorylation and limits Th17 differentiation. MINK1-deficient mice showed enhanced Th17 responses and exacerbated experimental autoimmune encephalomyelitis (EAE).\",\n      \"method\": \"Direct phosphorylation assay (MINK1 phosphorylating SMAD2 at T324), MINK1 knockout mice, EAE model, ROS treatment assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct phosphorylation of identified residue (T324) demonstrated, in vivo genetic knockout with defined phenotype, ROS-MINK1-SMAD2 axis established with multiple methods\",\n      \"pmids\": [\"28400474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAP4K4, MINK1, and TNIK act redundantly as upstream regulators of the DLK/JNK signaling pathway in neurons. These MAP4Ks regulate DLK activation and downstream JNK-dependent phosphorylation of c-Jun in response to trophic factor withdrawal. Pharmacological inhibition of MAP4Ks blocks stabilization and phosphorylation of DLK within axons and subsequent retrograde translocation of the JNK signaling complex to the nucleus. Targeting all three kinases together (but not individually) protects neurons from degeneration.\",\n      \"method\": \"siRNA knockdown in embryonic DRG neurons, pharmacological inhibition, phosphorylation assays for DLK and c-Jun, axon retrograde signaling assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by genetic knockdown and pharmacological inhibition, defined pathway position (upstream of DLK), multiple orthogonal readouts (DLK phosphorylation, c-Jun phosphorylation, retrograde transport, neuronal survival)\",\n      \"pmids\": [\"28993483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MINK1 plays an essential role in platelet function, hemostasis, and thrombus formation. MINK1-deficient mice showed prolonged bleeding times, delayed arterial thrombosis, impaired platelet aggregation and secretion, and reduced spreading on fibrinogen. The functional defects were attributed to impaired ADP secretion and associated with reduced ERK, p38, and Akt signaling in platelets.\",\n      \"method\": \"MINK1 knockout mice, tail-bleeding assay, ferric chloride-induced thrombosis model, microfluidic whole-blood perfusion assay, platelet aggregation and spreading assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple defined in vivo and ex vivo phenotypes, ADP secretion identified as mechanistic basis, signaling pathway components identified\",\n      \"pmids\": [\"26598717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MINK1 directly phosphorylates NLRP3 at Ser725 (human/mouse), a modification required for priming of NLRP3 inflammasome activation in macrophages. The interaction depends on direct binding between MINK1 and the NLRP3 LRR domain. ROS upregulate MINK1 kinase activity to promote this phosphorylation event. MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis.\",\n      \"method\": \"In vitro kinase assay (direct phosphorylation of Ser725), co-immunoprecipitation (MINK1-NLRP3 LRR domain interaction), MINK1 knockout mice, sepsis and peritonitis models, ASC oligomerization and caspase activity assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct phosphorylation assay identifying specific residue, domain-level interaction mapping, in vivo knockout with multiple phenotypic readouts, ROS-MINK1-NLRP3 axis established\",\n      \"pmids\": [\"34480147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MINK1 phosphorylates glucocorticoid receptor (GR) at Thr524, which induces binding of 14-3-3 proteins (specifically 14-3-3ζ) to the GR ligand-binding domain. Cell-based approaches confirmed the importance of GR Thr524, GR S617, and MINK1 in inducing GR-14-3-3 binding. MINK1 was identified as the specific kinase for T524 by kinase screen.\",\n      \"method\": \"Kinase screen, phosphorylated GR peptide binding assays, biophysical studies (SPR/TR-FRET), X-ray crystallography of 14-3-3ζ with phospho-GR peptide, cell-based co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — kinase screen identifying MINK1, X-ray crystal structure of downstream complex, cell-based validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33744286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MINK1 phosphorylates LL5β (PHLDB2), promoting its interaction with CLASP proteins to trigger focal adhesion disassembly. MINK1 enzymatic activity is required for PRICKLE1-LL5β complex assembly and localization, and for cell migration. A phosphoproteomic strategy identified LL5β as a MINK1 substrate alongside PRICKLE1.\",\n      \"method\": \"Phosphoproteomics (MINK1 substrate identification), kinase inhibitor studies, co-immunoprecipitation, cell migration assays, focal adhesion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomic substrate identification plus functional validation with kinase inhibitor and protein complex assays, single lab\",\n      \"pmids\": [\"35971817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MINK1 modulates AKT phosphorylation at Ser473, enabling p-MDM2 (Ser166)-mediated degradation of p53. MINK1 was identified by CRISPR/Cas9 kinome knockout screening as a mediator of 5FU resistance in OSCC. An antibody-based phosphorylation array revealed MINK1 as a negative regulator of p53 through the AKT/MDM2 axis.\",\n      \"method\": \"CRISPR/Cas9 kinome knockout screen, phosphorylation antibody array, xenograft models (nude mice and zebrafish), western blot for AKT/MDM2/p53 signaling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide functional screen plus phosphorylation array identifying pathway, in vivo xenograft validation, single lab but multiple readouts\",\n      \"pmids\": [\"36182968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MINK1 deficiency protects cartilage from degeneration in aging joints through increased SMAD2 phosphorylation (pSMAD2) in chondrocytes, while accelerating OA progress in injury-induced model through enhanced osteogenesis of MSCs in the subchondral bone. Overexpression of MINK1 inhibited SMAD2 phosphorylation in vitro, confirming MINK1 as a negative regulator of TGFβ/SMAD2 signaling.\",\n      \"method\": \"MINK1 knockout mice (Mink1-/-), aging-related OA and DMM models, in vitro SMAD2 phosphorylation inhibition assay with MINK1 overexpression, immunohistochemistry\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation assay plus in vivo knockout models with defined phenotypes, single lab\",\n      \"pmids\": [\"31647983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MINK1 protein architecture comprises four domains: an N-terminal kinase domain, a coiled-coil region, a proline-rich region, and a C-terminal GCK domain. Yeast two-hybrid screening identified proteins interacting with the coiled-coil and proline-rich domains of MINK1 that implicate MINK1 in cytoskeletal organization, cell-cycle control, and apoptosis.\",\n      \"method\": \"Computational fold recognition/threading, yeast two-hybrid screen, gene expression analysis of yeast homologs, homology modeling of kinase domain\",\n      \"journal\": \"Current medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational prediction with yeast two-hybrid as supporting evidence; no direct biochemical validation of identified interactions\",\n      \"pmids\": [\"15032605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A de novo balanced translocation disrupting MINK1 between exon 1 and exon 2 (on chromosome 17p13) resulted in >50% reduction in MINK1 expression in patient-derived neural cells. Pathway analysis revealed enrichment of altered neural pathways, implicating MINK1 as a candidate monogenic disease gene for autism, epilepsy, and osteoporosis.\",\n      \"method\": \"Long-read genome sequencing, optical mapping, transcriptome sequencing of iPSC-derived neuroepithelial stem cells, pathway analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient, loss-of-function by haploinsufficiency with pathway analysis only; no direct mechanistic experiment linking MINK1 to the neural pathways identified\",\n      \"pmids\": [\"36012658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mink1 regulates canonical Wnt signaling to define cell fates of the Spemann Organizer and the Left-Right Organizer in Xenopus embryos, required for proper heart development. Unbiased proteomics identified Hmga2 as a downstream target of Mink1; Hmga2 can induce Spemann Organizer cell fates even when β-catenin is depleted, placing it downstream of Mink1 in a β-catenin-independent manner.\",\n      \"method\": \"Xenopus loss-of-function experiments, unbiased proteomics (Mink1 target identification), rescue experiments with Hmga2, β-catenin depletion\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in Xenopus with defined developmental phenotype, proteomics-based substrate identification, epistasis established between Mink1 and Hmga2, single lab\",\n      \"pmids\": [\"36572140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Resveratrol reduces cellular miR-17-5p levels, leading to MINK1 upregulation (miR-17-5p directly targets MINK1), which activates the JNK/c-Jun signaling cascade, ultimately upregulating ULBP2 expression on breast cancer cells and enhancing NK cell cytotoxicity. MINK1 knockdown and overexpression experiments in cells confirmed MINK1's role in facilitating JNK and c-Jun activation downstream of miR-17-5p.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-17-5p targeting MINK1), MINK1 knockdown/overexpression, JNK inhibitor (SP600125), flow cytometry, in vitro and in vivo NK cytotoxicity assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirming direct targeting, knockdown and overexpression with defined signaling readouts (JNK/c-Jun), in vivo validation, single lab\",\n      \"pmids\": [\"39963142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MINK1 deficiency triggers NF-κB signaling in nucleus pulposus (NP) tissues, leading to increased NP cell pyroptosis and exacerbated intervertebral disc degeneration. In common carp, the MINK1 homolog CcMINK1 interacts with NLRP3 via its S_TKC domain and facilitates NLRP3 phosphorylation, promoting NLRP3 aggregation and activation.\",\n      \"method\": \"MINK1 knockout mouse models (aging-induced and LSI surgery-induced IVD degeneration), co-immunoprecipitation (CcMINK1-CcNLRP3), overexpression studies, NF-κB pathway analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mammalian data is predominantly phenotypic (KO mice with NF-κB activation); direct mechanistic data (S_TKC domain binding, phosphorylation) is from fish ortholog only\",\n      \"pmids\": [\"38723371\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MINK1 (MAP4K6) is a Ste20-family serine/threonine kinase that functions as an upstream activator of DLK/JNK signaling in neurons (redundantly with MAP4K4 and TNIK), directly phosphorylates SMAD2 (T324) to suppress Th17 differentiation, phosphorylates NLRP3 (Ser725) to prime inflammasome activation in macrophages, phosphorylates Prickle to regulate its endosomal trafficking in Wnt/PCP signaling, phosphorylates the glucocorticoid receptor (T524) to recruit 14-3-3 proteins, phosphorylates LL5β to facilitate focal adhesion disassembly and cell migration, modulates AKT/MDM2/p53 signaling to influence chemoresistance, and is a component of the STRIPAK complex through direct interaction with STRN4, where PP2A activity within STRIPAK downregulates MINK1 kinase activity and MINK1 itself is required for cytokinesis completion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MINK1 (MAP4K6) is a Ste20-family serine/threonine kinase that couples upstream signals — frequently reactive oxygen species — to substrate phosphorylation across immune, developmental, cytoskeletal, and cell-division programs [#2, #5]. In innate immunity it directly phosphorylates NLRP3 at Ser725 through engagement of the NLRP3 LRR domain to prime inflammasome activation in macrophages, with ROS upregulating MINK1 activity, such that MINK1 loss blunts inflammatory responses in sepsis and peritonitis [#5]. In adaptive immunity ROS-activated MINK1 phosphorylates SMAD2 at Thr324 to inhibit TGF-β-induced SMAD2 activation and restrain Th17 differentiation, with MINK1-deficient mice showing exacerbated autoimmune encephalomyelitis [#2]; this same negative regulation of SMAD2 phosphorylation operates in chondrocytes [#9]. MINK1 also acts redundantly with MAP4K4 and TNIK as an upstream activator of DLK/JNK signaling in neurons, controlling DLK stabilization, c-Jun phosphorylation, and retrograde injury signaling [#3]. In Wnt/planar cell polarity signaling it phosphorylates Prickle on a conserved threonine to direct Rab5-dependent endosomal trafficking and membrane accumulation [#1], and through phosphorylation of LL5β (PHLDB2) it promotes CLASP recruitment, PRICKLE1–LL5β complex assembly, focal adhesion disassembly, and cell migration [#7]. MINK1 phosphorylates the glucocorticoid receptor at Thr524 to recruit 14-3-3ζ to its ligand-binding domain [#6], and it is a STRIPAK-complex component that binds STRN4 — whose associated PP2A downregulates MINK1 kinase activity — with MINK1 being required to complete cytokinesis at abscission [#0]. A de novo balanced translocation reducing MINK1 expression has been described as a candidate monogenic basis for autism, epilepsy, and osteoporosis [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before functional characterization, the question was what protein architecture and interaction surfaces MINK1 presents; domain dissection defined a kinase domain, coiled-coil, proline-rich region, and GCK domain with interactors implicating cytoskeleton, cell cycle, and apoptosis.\",\n      \"evidence\": \"Computational fold recognition and yeast two-hybrid screening of coiled-coil and proline-rich domains\",\n      \"pmids\": [\"15032605\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Interactions predicted but not biochemically validated\", \"No catalytic substrate identified\", \"Functional roles inferred only from interactor identity\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing MINK1 as a direct kinase in a defined pathway, it was shown to phosphorylate Prickle on a conserved threonine to govern Rab5-dependent endosomal trafficking in Wnt/PCP signaling.\",\n      \"evidence\": \"Mass spectrometry, in vitro kinase assay, and genetic interaction in Drosophila and Xenopus\",\n      \"pmids\": [\"22037766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite residue not mapped to a specific number\", \"Mechanism linking phosphorylation to trafficking incomplete\", \"Mammalian PCP relevance not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"To place MINK1 in a regulatory complex and the cell cycle, it was identified as a STRIPAK subunit bound to STRN4 whose PP2A activity suppresses MINK1, and required for abscission-stage cytokinesis.\",\n      \"evidence\": \"STRIPAK mass spectrometry, co-immunoprecipitation, and siRNA with time-lapse microscopy\",\n      \"pmids\": [\"22665485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytokinesis substrate of MINK1 not identified\", \"Mechanism of PP2A-mediated MINK1 inactivation unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Addressing MINK1 in vivo physiology, knockout mice revealed an essential role in platelet function, hemostasis, and thrombosis tied to impaired ADP secretion and reduced ERK/p38/Akt signaling.\",\n      \"evidence\": \"Knockout mice with bleeding, thrombosis, aggregation, and spreading assays\",\n      \"pmids\": [\"26598717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct platelet substrate of MINK1 not defined\", \"Connection between MINK1 and the ERK/p38/Akt readouts mechanistically unmapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies defined MINK1 as a ROS-responsive negative regulator of immunity, directly phosphorylating SMAD2 at Thr324 to limit Th17 differentiation, and as a redundant upstream activator of neuronal DLK/JNK signaling.\",\n      \"evidence\": \"Direct phosphorylation assays, knockout mice, EAE model, and DRG neuron knockdown/inhibition with DLK and c-Jun readouts\",\n      \"pmids\": [\"28400474\", \"28993483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ROS sensing by MINK1 not resolved\", \"Redundancy with MAP4K4/TNIK obscures individual neuronal contribution\", \"Direct DLK substrate relationship not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MINK1 was shown to phosphorylate NLRP3 at Ser725 via the LRR domain to prime inflammasome activation, and to phosphorylate the glucocorticoid receptor at Thr524 to recruit 14-3-3ζ, broadening its direct-substrate repertoire.\",\n      \"evidence\": \"In vitro kinase assays, domain-mapped co-IP, knockout sepsis/peritonitis models, kinase screen, and X-ray crystallography of 14-3-3ζ with phospho-GR peptide\",\n      \"pmids\": [\"34480147\", \"33744286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activation of MINK1 in macrophages partially defined (ROS) but signaling input unclear\", \"Functional consequence of GR Thr524 phosphorylation on transcription not fully characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanding MINK1's cytoskeletal and oncogenic roles, it was found to phosphorylate LL5β to drive focal adhesion disassembly and migration, to suppress p53 via AKT/MDM2 conferring chemoresistance, and to regulate canonical Wnt fate decisions through the downstream target Hmga2.\",\n      \"evidence\": \"Phosphoproteomics, kinase-inhibitor and migration assays, CRISPR kinome screen with phospho-array and xenografts, and Xenopus loss-of-function with proteomics and Hmga2 rescue\",\n      \"pmids\": [\"35971817\", \"36182968\", \"36572140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MINK1 directly phosphorylates AKT pathway components or acts indirectly is unresolved\", \"Hmga2 regulation mechanism downstream of MINK1 not defined\", \"Single-lab findings per role\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A candidate human disease link emerged from a de novo translocation reducing MINK1 expression, implicating haploinsufficiency in autism, epilepsy, and osteoporosis.\",\n      \"evidence\": \"Long-read genome sequencing, optical mapping, and transcriptomics of patient iPSC-derived neuroepithelial cells\",\n      \"pmids\": [\"36012658\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single patient with pathway analysis only\", \"No mechanistic experiment linking MINK1 loss to the neural phenotypes\", \"Causality versus correlation not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MINK1's inflammasome and degenerative roles were extended to intervertebral disc degeneration, where deficiency triggers NF-κB-driven NP cell pyroptosis, with direct NLRP3-domain interaction shown only in a fish ortholog.\",\n      \"evidence\": \"Knockout mouse IVD degeneration models with NF-κB analysis and CcMINK1–CcNLRP3 co-IP in common carp\",\n      \"pmids\": [\"38723371\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mammalian direct NLRP3 interaction not demonstrated here\", \"Mechanistic data restricted to fish ortholog\", \"Phenotypic mammalian data only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A regulatory axis upstream of MINK1 was defined in which miR-17-5p directly targets MINK1, and MINK1 activates JNK/c-Jun to upregulate ULBP2 and enhance NK cytotoxicity against breast cancer cells.\",\n      \"evidence\": \"Dual-luciferase reporter, MINK1 knockdown/overexpression with JNK inhibition, flow cytometry, and in vivo NK cytotoxicity\",\n      \"pmids\": [\"39963142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MINK1 substrate in JNK activation not identified\", \"Generalizability beyond breast cancer context unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MINK1 substrate selection is governed across its diverse contexts — and how a single ROS-activated kinase is partitioned between inflammasome priming, SMAD2 inhibition, DLK/JNK activation, PCP trafficking, and cytokinesis — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model of context-specific substrate targeting\", \"STRIPAK/PP2A regulation not integrated with the various effector pathways\", \"Direct human disease causation unconfirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5, 6, 7]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"STRIPAK\"],\n    \"partners\": [\"STRN4\", \"NLRP3\", \"SMAD2\", \"PRICKLE1\", \"PHLDB2\", \"NR3C1\", \"YWHAZ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}