id: Q9NYL2 gene_symbol: MAP3K20 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: MAP3K20 (ZAK; also MLK7/MRK) is a stress-activated mitogen-activated protein kinase kinase kinase (MAP3K) of the MLK family. As a serine/threonine protein kinase it phosphorylates the MAP2Ks MKK4/MKK7 (activating JNK) and MKK3/MKK6 (activating p38), driving stress-activated MAPK (JNK and p38) signaling that can promote programmed cell death. The principal isoform ZAKalpha is the proximal sensor of the ribotoxic stress response and directly binds the ribosome by inserting its flexible C-terminus into the intersubunit space (contacting helix 14 of 18S rRNA), acting as a sentinel for colliding ribosomes. Ribosome collisions trigger MAP3K20 autophosphorylation and activation; depending on collision severity it either activates the JNK/p38 cascade to promote cell death or activates EIF2AK4/GCN2 to engage the integrated stress response. ZAKalpha also drives the UV-B-induced NLRP1 inflammasome and pyroptosis by phosphorylating NLRP1. A shorter isoform, ZAKbeta, lacks the ribosome-binding C-terminus and does not sense collisions. MAP3K20 localizes mainly to the cytoplasm/cytosol (with reported nuclear pools and histone H3 Ser-28 kinase activity). It has additional reported roles in DNA-damage checkpoint signaling and cardiac stress responses. Biallelic variants cause split-foot malformation with mesoaxial polydactyly (SFMMP) and centronuclear myopathy 6 (CNM6). alternative_products: - name: ZAKalpha id: Q9NYL2-1 - name: ZAKbeta (Beta, MLK7) id: Q9NYL2-2 sequence_note: VSP_051743, VSP_051744 - name: Isoform 3 (HCCS-4) id: Q9NYL2-3 sequence_note: VSP_051741, VSP_051742 existing_annotations: - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: MAP3K20 is a serine/threonine protein kinase; this is one of its core molecular functions, well supported experimentally and phylogenetically. action: ACCEPT reason: Directly demonstrated kinase activity (multiple EXP/IDA) and consistent with phylogenetic inference; a core function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: MAP3K20 is active in the cytosol, where it senses ribosome collisions and phosphorylates MAP2Ks; well supported. action: ACCEPT reason: Cytosolic activity is consistent with experimental localization and the ribosome-associated sensing function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Cytoplasm, cytosol - term: id: GO:0007059 label: chromosome segregation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic annotation of chromosome segregation transferred from a PANTHER node that includes NEK6 (Q9HC98). There is no direct experimental evidence that MAP3K20 functions in chromosome segregation. action: MARK_AS_OVER_ANNOTATED reason: This IBA derives from a tree node shared with NEK6 and is not supported by MAP3K20-specific evidence; MAP3K20's documented roles are stress-activated MAPK signaling and ribotoxic stress sensing. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-goa.tsv supporting_text: PANTHER:PTN002878623|UniProtKB:Q9HC98 - term: id: GO:0030071 label: regulation of mitotic metaphase/anaphase transition evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic annotation transferred from a node including NEK6; no MAP3K20-specific evidence for a role in the metaphase/anaphase transition. action: MARK_AS_OVER_ANNOTATED reason: Like the chromosome-segregation IBA, this is transferred from a NEK6-containing node and is not supported by MAP3K20-specific data. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-goa.tsv supporting_text: PANTHER:PTN002878623|UniProtKB:Q9HC98 - term: id: GO:0004672 label: protein kinase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based protein kinase activity, a broad parent of the specific serine/threonine and MAP3K activities of MAP3K20. action: ACCEPT reason: Correct but general; the specific MF terms (protein serine/threonine kinase, MAP kinase kinase kinase) are more informative and also annotated. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0004709 label: MAP kinase kinase kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: MAP3K20 is a MAP kinase kinase kinase that phosphorylates MKK3/4/6/7; a core molecular function, well supported experimentally. action: ACCEPT reason: Directly demonstrated MAP3K activity (multiple IDA); core function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: ATP binding by the kinase domain, required for catalysis; directly demonstrated experimentally. action: ACCEPT reason: Standard, experimentally supported catalytic cofactor binding for a protein kinase. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: ATP binding - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic nuclear localization; MAP3K20 has reported nuclear pools and histone H3 Ser-28 kinase activity, but its predominant compartment is the cytoplasm. action: KEEP_AS_NON_CORE reason: Nuclear localization is reported (and consistent with histone-kinase activity) but is secondary to MAP3K20's predominant cytoplasmic localization and ribosome-associated function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: histone kinase by phosphorylating histone H3 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic cytoplasmic localization, consistent with the predominant compartment. action: ACCEPT reason: Agrees with EXP/IDA cytoplasm/cytosol localization. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000116 qualifier: enables review: summary: RHEA/EC-based protein serine kinase activity, consistent with MAP3K20's serine/threonine kinase function. action: ACCEPT reason: Correct and supported by multiple EXP annotations; a core catalytic function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15778465 qualifier: enables review: summary: IntAct interaction with 14-3-3 sigma/SFN (P31947). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative and not a core molecular function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'Q9NYL2; P31947: SFN' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16189514 qualifier: enables review: summary: IntAct interaction with ZNF567 (Q8N184). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'Q8N184: ZNF567' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21516116 qualifier: enables review: summary: IntAct interaction with ZNF567 (Q8N184). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'Q8N184: ZNF567' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21988832 qualifier: enables review: summary: IntAct interactions with RPS6KA5 (O75582) and a 14-3-3 protein (P63104/YWHAZ). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'Q9NYL2; O75582: RPS6KA5' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: IntAct interaction with the 14-3-3 protein YWHAZ (P63104). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'P63104: YWHAZ' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 qualifier: enables review: summary: IntAct interaction with ZNF567 (Q8N184). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'Q8N184: ZNF567' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex interaction with the 14-3-3 protein YWHAZ (P63104). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'P63104: YWHAZ' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: IntAct interaction with the 14-3-3 protein YWHAZ (P63104). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'P63104: YWHAZ' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36931259 qualifier: enables review: summary: IntAct interactions with 14-3-3 proteins SFN (P31947) and YWHAZ (P63104). The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding is uninformative and not core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'Q9NYL2; P31947: SFN' - term: id: GO:0000287 label: magnesium ion binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Magnesium binding by the kinase domain, required for phosphotransfer; directly demonstrated experimentally. action: ACCEPT reason: Standard catalytic cofactor binding for a protein kinase, with IDA support. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Ortholog-transferred serine/threonine kinase activity, corroborated by direct evidence; a core molecular function. action: ACCEPT reason: Agrees with multiple EXP/IDA annotations of kinase activity. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0007254 label: JNK cascade evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: MAP3K20 activates the JNK cascade by phosphorylating MKK4/MKK7; well supported experimentally. action: ACCEPT reason: Directly demonstrated JNK-cascade activation (multiple IDA); a core biological process. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0035556 label: intracellular signal transduction evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Broad intracellular signal transduction; MAP3K20 is a signaling kinase, but more specific MAPK-cascade terms are preferable. action: KEEP_AS_NON_CORE reason: Correct but general; the specific JNK/p38/stress-activated MAPK cascade terms capture the role more precisely. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0038066 label: p38MAPK cascade evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: MAP3K20 activates the p38 cascade by phosphorylating MKK3/MKK6; well supported experimentally. action: ACCEPT reason: Directly demonstrated p38-cascade activation (multiple IDA); a core biological process. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the JNK and MAP kinase p38 - term: id: GO:0042733 label: embryonic digit morphogenesis evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Electronic annotation of embryonic digit morphogenesis, corroborated by the human disease phenotype (split-foot malformation) and IMP evidence. action: KEEP_AS_NON_CORE reason: Supported by the SFMMP disease phenotype and IMP evidence, but a developmental outcome downstream of MAP3K20's core kinase/stress-signaling function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Split-foot malformation with mesoaxial polydactyly - term: id: GO:0051403 label: stress-activated MAPK cascade evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: MAP3K20 is a stress-activated component driving the JNK/p38 (stress-activated MAPK) cascade; a core biological process. action: ACCEPT reason: Strongly supported by experimental evidence (ribotoxic stress, osmotic shock, ionizing radiation); core process. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Stress-activated component of a protein kinase signal - term: id: GO:0060173 label: limb development evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog/IMP-supported role in limb development, consistent with the split-foot malformation phenotype. A developmental outcome. action: KEEP_AS_NON_CORE reason: Supported by disease genetics but downstream of MAP3K20's core kinase function; non-core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Split-foot malformation with mesoaxial polydactyly - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) cytosolic localization, consistent with the predominant compartment and ribosome-associated function. action: ACCEPT reason: IDA-supported cytosolic localization agrees with the documented site of action. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Cytoplasm, cytosol - term: id: GO:0005634 label: nucleus evidence_type: EXP original_reference_id: PMID:15684425 qualifier: located_in review: summary: Experimental nuclear localization, associated with MAP3K20 histone H3 Ser-28 kinase activity. A secondary localization. action: KEEP_AS_NON_CORE reason: Experimentally documented nuclear pool (histone-kinase context) but secondary to the predominant cytoplasmic localization. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: histone kinase by phosphorylating histone H3 - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:15684425 qualifier: located_in review: summary: Experimental cytoplasmic localization, the predominant compartment. action: ACCEPT reason: Direct experimental support for cytoplasmic localization. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:11836244 qualifier: enables review: summary: Experimentally demonstrated serine kinase activity (original MRK/ZAK characterization). action: ACCEPT reason: Direct experimental support for the core catalytic function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:14521931 qualifier: enables review: summary: Experimentally demonstrated serine kinase activity. action: ACCEPT reason: Direct experimental support for the core catalytic function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:26999302 qualifier: enables review: summary: Experimentally demonstrated serine kinase activity. action: ACCEPT reason: Direct experimental support for the core catalytic function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:32289254 qualifier: enables review: summary: Experimentally demonstrated serine kinase activity (ZAKalpha ribotoxic stress study). action: ACCEPT reason: Direct experimental support for the core catalytic function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:32610081 qualifier: enables review: summary: Experimentally demonstrated serine kinase activity (ribosome-collision cell-fate study). action: ACCEPT reason: Direct experimental support for the core catalytic function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:35857590 qualifier: enables review: summary: Experimentally demonstrated serine kinase activity (NLRP1 inflammasome study). action: ACCEPT reason: Direct experimental support for the core catalytic function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0000165 label: MAPK cascade evidence_type: IDA original_reference_id: PMID:18331592 qualifier: involved_in review: summary: MAP3K20 functions in the MAPK cascade; supported by direct evidence. action: ACCEPT reason: Directly demonstrated involvement in MAPK signaling; consistent with the core role, though the specific JNK/p38 cascade terms are more precise. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0006954 label: inflammatory response evidence_type: IMP original_reference_id: PMID:18331592 qualifier: involved_in review: summary: MAP3K20 contributes to inflammatory signaling (consistent with its later-established role in the NLRP1 inflammasome/pyroptosis). action: KEEP_AS_NON_CORE reason: A genuine downstream outcome of MAP3K20 stress signaling, but broad; the specific pyroptotic/NLRP1 role is captured by other terms. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the NLRP1 inflammasome and subsequent - term: id: GO:0051403 label: stress-activated MAPK cascade evidence_type: IDA original_reference_id: PMID:20559024 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade; a core process. action: ACCEPT reason: Directly demonstrated stress-activated MAPK signaling. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Stress-activated component of a protein kinase signal - term: id: GO:0004706 label: JUN kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:14521931 qualifier: enables review: summary: MAP3K20 acts as a JNK kinase kinase (phosphorylating MKK4/MKK7 upstream of JNK); a specific, core molecular function. action: ACCEPT reason: Directly demonstrated JNKKK activity; a precise, core MF. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0004709 label: MAP kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:15737997 qualifier: enables review: summary: Direct evidence for MAP kinase kinase kinase activity; a core molecular function. action: ACCEPT reason: Directly demonstrated MAP3K activity. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0007254 label: JNK cascade evidence_type: IDA original_reference_id: PMID:14521931 qualifier: involved_in review: summary: Direct evidence for MAP3K20 activation of the JNK cascade; a core process. action: ACCEPT reason: Directly demonstrated JNK-cascade involvement. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0007254 label: JNK cascade evidence_type: IDA original_reference_id: PMID:15737997 qualifier: involved_in review: summary: Direct evidence for MAP3K20 activation of the JNK cascade. action: ACCEPT reason: Directly demonstrated JNK-cascade involvement. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0038066 label: p38MAPK cascade evidence_type: IDA original_reference_id: PMID:15737997 qualifier: involved_in review: summary: Direct evidence for MAP3K20 activation of the p38 cascade. action: ACCEPT reason: Directly demonstrated p38-cascade involvement. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the JNK and MAP kinase p38 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:35857590 qualifier: enables review: summary: Direct evidence for serine/threonine kinase activity (NLRP1 study); core molecular function. action: ACCEPT reason: Directly demonstrated kinase activity. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0004706 label: JUN kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:32610081 qualifier: enables review: summary: Direct evidence for JNKKK activity in the ribosome-collision cell-fate study. action: ACCEPT reason: Directly demonstrated JNKKK activity; core MF. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0004709 label: MAP kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:32289254 qualifier: enables review: summary: Direct evidence for MAP3K activity in the ZAKalpha ribotoxic stress study. action: ACCEPT reason: Directly demonstrated MAP3K activity; core MF. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0004709 label: MAP kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:32610081 qualifier: enables review: summary: Direct evidence for MAP3K activity in the ribosome-collision cell-fate study. action: ACCEPT reason: Directly demonstrated MAP3K activity; core MF. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0004709 label: MAP kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:35857590 qualifier: enables review: summary: Direct evidence for MAP3K activity in the NLRP1 inflammasome study. action: ACCEPT reason: Directly demonstrated MAP3K activity; core MF. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0007254 label: JNK cascade evidence_type: IDA original_reference_id: PMID:32610081 qualifier: involved_in review: summary: Direct evidence for JNK-cascade activation upon ribosome collisions. action: ACCEPT reason: Directly demonstrated JNK-cascade involvement in ribotoxic stress. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0030295 label: protein kinase activator activity evidence_type: IDA original_reference_id: PMID:32610081 qualifier: enables review: summary: MAP3K20 activates EIF2AK4/GCN2 independently of its own kinase activity, acting as a protein kinase activator in the integrated stress response branch. action: ACCEPT reason: Directly demonstrated; MAP3K20 activates GCN2 kinase-independently, a genuine and distinctive molecular function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: MAP3K20 activates EIF2AK4/GCN2 - term: id: GO:0031098 label: stress-activated protein kinase signaling cascade evidence_type: IDA original_reference_id: PMID:35857590 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in stress-activated protein kinase signaling (NLRP1/ribotoxic stress); a core process. action: ACCEPT reason: Directly demonstrated stress-activated signaling. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Stress-activated component of a protein kinase signal - term: id: GO:0038066 label: p38MAPK cascade evidence_type: IDA original_reference_id: PMID:32610081 qualifier: involved_in review: summary: Direct evidence for p38-cascade activation upon ribosome collisions. action: ACCEPT reason: Directly demonstrated p38-cascade involvement in ribotoxic stress. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the JNK and MAP kinase p38 - term: id: GO:0038066 label: p38MAPK cascade evidence_type: IDA original_reference_id: PMID:35857590 qualifier: involved_in review: summary: Direct evidence for p38-cascade activation in the NLRP1/ribotoxic stress study. action: ACCEPT reason: Directly demonstrated p38-cascade involvement. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the JNK and MAP kinase p38 - term: id: GO:0043022 label: ribosome binding evidence_type: IDA original_reference_id: PMID:32289254 qualifier: enables review: summary: ZAKalpha directly binds the ribosome by inserting its flexible C-terminus into the intersubunit space, acting as the collision sensor; a core, distinctive molecular function. action: ACCEPT reason: Directly demonstrated ribosome binding underlying the ribotoxic-stress sensor role; core MF for ZAKalpha. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: directly binds to the ribosome by inserting its - term: id: GO:0043022 label: ribosome binding evidence_type: IDA original_reference_id: PMID:32610081 qualifier: enables review: summary: ZAKalpha binds the ribosome and preferentially associates with colliding ribosomes; core sensor function. action: ACCEPT reason: Directly demonstrated ribosome binding; core MF for the sensor role. supported_by: - reference_id: PMID:32610081 supporting_text: ZAKα preferentially associates with colliding ribosomes relative to monosomes. - term: id: GO:0043068 label: positive regulation of programmed cell death evidence_type: IDA original_reference_id: PMID:32289254 qualifier: acts_upstream_of review: summary: MAP3K20 acts upstream of programmed cell death triggered by dangerous levels of ribosome collisions (via JNK/p38). action: ACCEPT reason: Directly demonstrated; MAP3K20 promotes programmed cell death in response to ribotoxic stress. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: pathways that promote programmed cell death - term: id: GO:0043068 label: positive regulation of programmed cell death evidence_type: IDA original_reference_id: PMID:32610081 qualifier: acts_upstream_of review: summary: MAP3K20 acts upstream of programmed cell death in the ribosome-collision cell-fate decision. action: ACCEPT reason: Directly demonstrated cell-death-promoting role downstream of ribosome collisions. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: pathways that promote programmed cell death - term: id: GO:0046777 label: protein autophosphorylation evidence_type: IDA original_reference_id: PMID:32289254 qualifier: involved_in review: summary: Ribosome collisions trigger MAP3K20 autophosphorylation and activation; directly demonstrated. action: ACCEPT reason: Directly demonstrated autophosphorylation, the activation step of the sensor. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: trigger the autophosphorylation and activation of - term: id: GO:0051403 label: stress-activated MAPK cascade evidence_type: IDA original_reference_id: PMID:32289254 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade (ribotoxic stress); a core process. action: ACCEPT reason: Directly demonstrated stress-activated MAPK signaling in the ribotoxic stress response. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Stress-activated component of a protein kinase signal - term: id: GO:0051403 label: stress-activated MAPK cascade evidence_type: IDA original_reference_id: PMID:32610081 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade (ribosome-collision study). action: ACCEPT reason: Directly demonstrated stress-activated MAPK signaling. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Stress-activated component of a protein kinase signal - term: id: GO:0070181 label: small ribosomal subunit rRNA binding evidence_type: IDA original_reference_id: PMID:32289254 qualifier: enables review: summary: ZAKalpha binds helix 14 of 18S rRNA in the small ribosomal subunit, the molecular basis of its ribosome-collision sensing. action: ACCEPT reason: Directly demonstrated 18S rRNA binding (helix 14); a precise, mechanistically important molecular function for the sensor. supported_by: - reference_id: PMID:32289254 supporting_text: ZAKα binds helix 14 of 18S ribosomal RNA (rRNA). - term: id: GO:0070269 label: pyroptotic inflammatory response evidence_type: IDA original_reference_id: PMID:35857590 qualifier: acts_upstream_of_positive_effect review: summary: ZAKalpha drives UV-B-induced pyroptosis by activating the NLRP1 inflammasome (directly phosphorylating NLRP1). action: ACCEPT reason: Directly demonstrated; MAP3K20 acts upstream of NLRP1-driven pyroptosis. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the NLRP1 inflammasome and subsequent - term: id: GO:0071493 label: cellular response to UV-B evidence_type: IDA original_reference_id: PMID:35857590 qualifier: involved_in review: summary: ZAKalpha mediates the cellular response to UV-B (ribosome collisions activate MAP3K20, which phosphorylates NLRP1). action: ACCEPT reason: Directly demonstrated UV-B-triggered MAP3K20 signaling; a genuine process. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: triggering the NLRP1 inflammasome in response to UV-B - term: id: GO:0140469 label: GCN2-mediated signaling evidence_type: IDA original_reference_id: PMID:32610081 qualifier: acts_upstream_of review: summary: MAP3K20 acts upstream of GCN2-mediated signaling, activating EIF2AK4/GCN2 (kinase-independently) to engage the integrated stress response. action: ACCEPT reason: Directly demonstrated; a distinctive role of MAP3K20 in routing ribosome-collision signals to the ISR via GCN2. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: MAP3K20 activates EIF2AK4/GCN2 - term: id: GO:0004706 label: JUN kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:12220515 qualifier: enables review: summary: Direct evidence for JNKKK activity; a precise, core molecular function. action: ACCEPT reason: Directly demonstrated JNKKK activity. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0007254 label: JNK cascade evidence_type: IDA original_reference_id: PMID:12220515 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in the JNK cascade. action: ACCEPT reason: Directly demonstrated JNK-cascade involvement. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0046777 label: protein autophosphorylation evidence_type: IDA original_reference_id: PMID:12220515 qualifier: involved_in review: summary: Direct evidence for MAP3K20 autophosphorylation, its activation mechanism. action: ACCEPT reason: Directly demonstrated autophosphorylation. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: trigger the autophosphorylation and activation of - term: id: GO:0004706 label: JUN kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:11836244 qualifier: enables review: summary: Direct evidence for JNKKK activity (original MRK/ZAK characterization). action: ACCEPT reason: Directly demonstrated JNKKK activity. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0007254 label: JNK cascade evidence_type: IDA original_reference_id: PMID:11836244 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in the JNK cascade. action: ACCEPT reason: Directly demonstrated JNK-cascade involvement. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Activates JNK through - term: id: GO:0038066 label: p38MAPK cascade evidence_type: IDA original_reference_id: PMID:11836244 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in the p38 cascade. action: ACCEPT reason: Directly demonstrated p38-cascade involvement. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the JNK and MAP kinase p38 - term: id: GO:1904291 label: positive regulation of mitotic DNA damage checkpoint evidence_type: IDA original_reference_id: PMID:15342622 qualifier: involved_in review: summary: MAP3K20 may regulate the S/G2 DNA-damage checkpoint via phosphorylation of CHEK2; a context-specific role. action: KEEP_AS_NON_CORE reason: Experimentally reported checkpoint role (CHEK2 phosphorylation) but distinct from MAP3K20's predominant stress-activated MAPK/ribotoxic-stress function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: regulation of S and G2 cell cycle - term: id: GO:0051403 label: stress-activated MAPK cascade evidence_type: IDA original_reference_id: PMID:11836244 qualifier: involved_in review: summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade. action: ACCEPT reason: Directly demonstrated stress-activated MAPK signaling; core process. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Stress-activated component of a protein kinase signal - term: id: GO:0071480 label: cellular response to gamma radiation evidence_type: IDA original_reference_id: PMID:11836244 qualifier: involved_in review: summary: MAP3K20 (MRK) mediates a response to gamma/ionizing radiation, consistent with its stress-activated role. action: KEEP_AS_NON_CORE reason: A genuine stress-response context but one of several stress stimuli; the ribotoxic stress / stress-activated MAPK cascade is the core. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: osmotic shock and ionizing - term: id: GO:0042733 label: embryonic digit morphogenesis evidence_type: IMP original_reference_id: PMID:26755636 qualifier: involved_in review: summary: Loss-of-function variants cause split-foot malformation, implicating MAP3K20 in embryonic digit morphogenesis. action: KEEP_AS_NON_CORE reason: Supported by human disease genetics (SFMMP) but a developmental outcome downstream of the core kinase function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Split-foot malformation with mesoaxial polydactyly - term: id: GO:0060173 label: limb development evidence_type: IMP original_reference_id: PMID:26755636 qualifier: involved_in review: summary: Loss-of-function variants cause limb/foot malformation, implicating MAP3K20 in limb development. action: KEEP_AS_NON_CORE reason: Supported by disease genetics but downstream of the core kinase function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Split-foot malformation with mesoaxial polydactyly - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22681889 qualifier: enables review: summary: High-throughput RNA-interactome capture annotated MAP3K20 as RNA-binding. This is consistent with (and likely reflects) its specific 18S rRNA / ribosome binding; the bare RNA binding term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Generic RNA binding from a proteome-wide screen; the biologically meaningful activity is the specific small ribosomal subunit rRNA binding (GO:0070181) already annotated. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: directly binds to the ribosome by inserting its - term: id: GO:0000077 label: DNA damage checkpoint signaling evidence_type: IMP original_reference_id: PMID:11836244 qualifier: involved_in review: summary: MAP3K20 (MRK) was implicated in DNA-damage checkpoint signaling after gamma irradiation; a context-specific role. action: KEEP_AS_NON_CORE reason: Reported checkpoint role, but distinct from and secondary to MAP3K20's predominant ribotoxic-stress / stress-activated MAPK function. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: regulation of S and G2 cell cycle - term: id: GO:0004709 label: MAP kinase kinase kinase activity evidence_type: IDA original_reference_id: PMID:11836244 qualifier: enables review: summary: Direct evidence for MAP3K activity (original MRK/ZAK characterization); core molecular function. action: ACCEPT reason: Directly demonstrated MAP3K activity. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0008219 label: cell death evidence_type: NAS original_reference_id: PMID:11836244 qualifier: involved_in review: summary: Broad cell-death annotation; MAP3K20 promotes programmed cell death in response to stress. The more specific positive regulation of programmed cell death is preferable. action: KEEP_AS_NON_CORE reason: Correct in spirit but a broad term; the specific programmed-cell-death terms capture the role. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: promotes programmed cell death - term: id: GO:0030154 label: cell differentiation evidence_type: NAS original_reference_id: PMID:11836244 qualifier: involved_in review: summary: Broad cell-differentiation annotation (non-author statement) with no specific MAP3K20 mechanism documented. action: MARK_AS_OVER_ANNOTATED reason: Very general NAS annotation not supported by specific MAP3K20 evidence; its documented roles are stress-activated signaling and ribotoxic stress sensing. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Stress-activated component of a protein kinase signal - term: id: GO:0000287 label: magnesium ion binding evidence_type: IDA original_reference_id: PMID:11836244 qualifier: enables review: summary: Direct evidence for magnesium binding by the kinase domain. action: ACCEPT reason: Standard catalytic cofactor binding, experimentally supported. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0005524 label: ATP binding evidence_type: IDA original_reference_id: PMID:11836244 qualifier: enables review: summary: Direct evidence for ATP binding by the kinase domain. action: ACCEPT reason: Standard catalytic cofactor binding, experimentally supported. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: ATP binding - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity-based cytoplasmic localization, consistent with the predominant compartment. action: ACCEPT reason: Agrees with experimental cytoplasm/cytosol localization. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0006468 label: protein phosphorylation evidence_type: IDA original_reference_id: PMID:11836244 qualifier: involved_in review: summary: MAP3K20 phosphorylates substrate proteins; protein phosphorylation is the direct process outcome of its kinase activity. action: ACCEPT reason: Directly supported process annotation for a protein kinase. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - term: id: GO:0043065 label: positive regulation of apoptotic process evidence_type: IDA original_reference_id: PMID:10924358 qualifier: involved_in review: summary: MAP3K20 positively regulates apoptosis in response to stress, consistent with its programmed-cell-death-promoting role. action: ACCEPT reason: Directly demonstrated pro-apoptotic role downstream of MAP3K20 stress signaling. supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: promotes programmed cell death references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000116 title: Gene Ontology annotation based on rule-based mapping of RHEA reactions to GO molecular functions findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10924358 title: 'Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif.' findings: [] - id: PMID:11836244 title: MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. findings: - statement: MRK/ZAK (MAP3K20) is a serine/threonine MAP3K that activates JNK and p38 and functions in gamma-radiation-induced cell-cycle arrest/checkpoint signaling. reference_section_type: ABSTRACT - id: PMID:12220515 title: 'Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest.' findings: [] - id: PMID:14521931 title: 'Effect of C-terminal truncations on MLK7 catalytic activity and JNK activation.' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Anchored to GOA: this PMID supports IDA annotations to GO:0004706 (JUN kinase kinase kinase activity) and GO:0004709 (MAP kinase kinase kinase activity), establishing MAP3K20/ZAK as a MAP3K driving the JNK cascade. Not cached; verification via GOA evidence codes for the core MF.' - id: PMID:15342622 title: 'The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway.' findings: [] - id: PMID:15684425 title: Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase alpha. findings: [] - id: PMID:15737997 title: 'Complete inhibition of anisomycin and UV radiation but not cytokine induced JNK and p38 activation by an aryl-substituted dihydropyrrolopyrazole quinoline and mixed lineage kinase 7 small interfering RNA.' findings: [] - id: PMID:15778465 title: Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer. findings: [] - id: PMID:16189514 title: Towards a proteome-scale map of the human protein-protein interaction network. findings: [] - id: PMID:18331592 title: 'ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-induced proinflammatory cytokine expression.' findings: [] - id: PMID:20559024 title: 'ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells.' findings: [] - id: PMID:21516116 title: Next-generation sequencing to generate interactome datasets. findings: [] - id: PMID:21988832 title: Toward an understanding of the protein interaction network of the human liver. findings: [] - id: PMID:22681889 title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. findings: [] - id: PMID:26755636 title: 'Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.' findings: - statement: Loss-of-function MAP3K20/ZAK variants cause split-foot malformation with mesoaxial polydactyly, implicating MAP3K20 in limb/digit development. reference_section_type: ABSTRACT - id: PMID:26999302 title: Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:31515488 title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. findings: [] - id: PMID:32289254 title: ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains. findings: - statement: ZAKalpha directly associates with ribosomes by inserting its flexible C-terminus into the intersubunit space and binds helix 14 of 18S rRNA; these sensor domains are required for ribotoxic stress response (RSR) activation. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Cached publication title matches the YAML title exactly; establishes ZAKalpha as the proximal sensor of stalled/colliding ribosomes. GOA IDA from this PMID supports GO:0004709 (MAP3K activity) and GO:0043022 (ribosome binding), the core sensor function.' - id: PMID:32610081 title: Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. findings: - statement: ZAKalpha senses ribosome collisions and, depending on severity, activates the stress-activated p38/JNK cascade (cell death) or EIF2AK4/GCN2-mediated integrated stress response (survival); it preferentially associates with colliding ribosomes. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Cached publication title matches the YAML title exactly; shows ZAKalpha senses ribosome collisions and bifurcates the stress response (p38/JNK death vs GCN2 survival). Supports the ribotoxic-stress core function.' - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] - id: PMID:35857590 title: ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome. findings: - statement: ZAKalpha-driven ribotoxic stress response (e.g. UV-B) activates the human NLRP1 inflammasome via direct NLRP1 phosphorylation, leading to pyroptosis. reference_section_type: ABSTRACT - id: PMID:36931259 title: A central chaperone-like role for 14-3-3 proteins in human cells. findings: [] core_functions: - description: Stress-activated serine/threonine MAP kinase kinase kinase that phosphorylates MAP2Ks (MKK4/MKK7 and MKK3/MKK6) to activate the JNK and p38 (stress-activated) MAPK cascades, driving stress responses that can promote programmed cell death. molecular_function: id: GO:0004709 label: MAP kinase kinase kinase activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: Acts by catalyzing phosphorylation of MAP kinase - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: leading to activation of the JNK and MAP kinase p38 - description: Proximal sensor of ribosome collisions in the ribotoxic stress response; isoform ZAKalpha directly binds the ribosome (inserting its C-terminus into the intersubunit space and contacting helix 14 of 18S rRNA), autophosphorylates upon collisions, and routes the signal to the JNK/p38 cell-death cascade or to GCN2-mediated integrated stress response. molecular_function: id: GO:0043022 label: ribosome binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: directly binds to the ribosome by inserting its - reference_id: PMID:32289254 supporting_text: ZAKα binds helix 14 of 18S ribosomal RNA (rRNA). - description: Stress-activated MAPK signaling that triggers programmed cell death and, in response to UV-B/ribotoxic stress, the NLRP1 inflammasome and pyroptosis through direct NLRP1 phosphorylation. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: triggering the NLRP1 inflammasome in response to UV-B - reference_id: file:human/MAP3K20/MAP3K20-uniprot.txt supporting_text: pathways that promote programmed cell death proposed_new_terms: [] suggested_questions: - question: What determines whether ribosome collisions sensed by ZAKalpha route to the pro-death JNK/p38 cascade versus the pro-survival GCN2/integrated stress response (e.g. collision density, duration, or ribosome ubiquitination state)? - question: How do the centronuclear myopathy (CNM6) and split-foot malformation (SFMMP) phenotypes relate mechanistically to defects in ribotoxic stress sensing versus other MAP3K20 functions? - question: Does the kinase-independent activation of GCN2 by MAP3K20 reflect a scaffolding interaction, and what is its structural basis? suggested_experiments: - description: Compare ZAKalpha (ribosome-binding) and ZAKbeta (C-terminus-deleted) knock-in cells for ribotoxic-stress-induced p38/JNK activation, GCN2/ISR engagement, and cell-fate outcomes to dissect collision-sensing-dependent versus -independent signaling. - description: Structure-guided mutations in the ZAKalpha C-terminal ribosome-sensing domains (intersubunit insertion; 18S rRNA helix-14 contact) tested for collision binding and downstream MAPK/NLRP1 activation. - description: Patient-derived myotubes carrying CNM6 variants assayed for ribotoxic stress signaling and proteostasis to test whether impaired ZAKalpha surveillance contributes to the myopathy.