Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004674 protein serine/threonine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: MAP3K20 is a serine/threonine protein kinase; this is one of its core molecular functions, well supported experimentally and phylogenetically. Reason: Directly demonstrated kinase activity (multiple EXP/IDA) and consistent with phylogenetic inference; a core function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: MAP3K20 is active in the cytosol, where it senses ribosome collisions and phosphorylates MAP2Ks; well supported. Reason: Cytosolic activity is consistent with experimental localization and the ribosome-associated sensing function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Cytoplasm, cytosol
GO:0007059 chromosome segregation	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/MAP3K20/MAP3K20-goa.tsv PANTHER:PTN002878623\|UniProtKB:Q9HC98
GO:0030071 regulation of mitotic metaphase/anaphase transition	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic annotation transferred from a node including NEK6; no MAP3K20-specific evidence for a role in the metaphase/anaphase transition. Reason: Like the chromosome-segregation IBA, this is transferred from a NEK6-containing node and is not supported by MAP3K20-specific data. Supporting Evidence: file:human/MAP3K20/MAP3K20-goa.tsv PANTHER:PTN002878623\|UniProtKB:Q9HC98
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based protein kinase activity, a broad parent of the specific serine/threonine and MAP3K activities of MAP3K20. Reason: Correct but general; the specific MF terms (protein serine/threonine kinase, MAP kinase kinase kinase) are more informative and also annotated. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0004709 MAP kinase kinase kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: MAP3K20 is a MAP kinase kinase kinase that phosphorylates MKK3/4/6/7; a core molecular function, well supported experimentally. Reason: Directly demonstrated MAP3K activity (multiple IDA); core function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: ATP binding by the kinase domain, required for catalysis; directly demonstrated experimentally. Reason: Standard, experimentally supported catalytic cofactor binding for a protein kinase. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt ATP binding
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic nuclear localization; MAP3K20 has reported nuclear pools and histone H3 Ser-28 kinase activity, but its predominant compartment is the cytoplasm. Reason: Nuclear localization is reported (and consistent with histone-kinase activity) but is secondary to MAP3K20's predominant cytoplasmic localization and ribosome-associated function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt histone kinase by phosphorylating histone H3
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Electronic cytoplasmic localization, consistent with the predominant compartment. Reason: Agrees with EXP/IDA cytoplasm/cytosol localization. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: RHEA/EC-based protein serine kinase activity, consistent with MAP3K20's serine/threonine kinase function. Reason: Correct and supported by multiple EXP annotations; a core catalytic function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0005515 protein binding	IPI PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ...	KEEP AS NON CORE	Summary: IntAct interaction with 14-3-3 sigma/SFN (P31947). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not a core molecular function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Q9NYL2; P31947: SFN
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	KEEP AS NON CORE	Summary: IntAct interaction with ZNF567 (Q8N184). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Q8N184: ZNF567
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	KEEP AS NON CORE	Summary: IntAct interaction with ZNF567 (Q8N184). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Q8N184: ZNF567
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	KEEP AS NON CORE	Summary: IntAct interactions with RPS6KA5 (O75582) and a 14-3-3 protein (P63104/YWHAZ). The bare protein binding term is uninformative. Reason: Records real interactions but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Q9NYL2; O75582: RPS6KA5
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: IntAct interaction with the 14-3-3 protein YWHAZ (P63104). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt P63104: YWHAZ
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	KEEP AS NON CORE	Summary: IntAct interaction with ZNF567 (Q8N184). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Q8N184: ZNF567
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex interaction with the 14-3-3 protein YWHAZ (P63104). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt P63104: YWHAZ
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	KEEP AS NON CORE	Summary: IntAct interaction with the 14-3-3 protein YWHAZ (P63104). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt P63104: YWHAZ
GO:0005515 protein binding	IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c...	KEEP AS NON CORE	Summary: IntAct interactions with 14-3-3 proteins SFN (P31947) and YWHAZ (P63104). The bare protein binding term is uninformative. Reason: Records real interactions but bare protein binding is uninformative and not core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Q9NYL2; P31947: SFN
GO:0000287 magnesium ion binding	IEA GO_REF:0000120	ACCEPT	Summary: Magnesium binding by the kinase domain, required for phosphotransfer; directly demonstrated experimentally. Reason: Standard catalytic cofactor binding for a protein kinase, with IDA support. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred serine/threonine kinase activity, corroborated by direct evidence; a core molecular function. Reason: Agrees with multiple EXP/IDA annotations of kinase activity. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0007254 JNK cascade	IEA GO_REF:0000120	ACCEPT	Summary: MAP3K20 activates the JNK cascade by phosphorylating MKK4/MKK7; well supported experimentally. Reason: Directly demonstrated JNK-cascade activation (multiple IDA); a core biological process. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0035556 intracellular signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad intracellular signal transduction; MAP3K20 is a signaling kinase, but more specific MAPK-cascade terms are preferable. Reason: Correct but general; the specific JNK/p38/stress-activated MAPK cascade terms capture the role more precisely. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0038066 p38MAPK cascade	IEA GO_REF:0000120	ACCEPT	Summary: MAP3K20 activates the p38 cascade by phosphorylating MKK3/MKK6; well supported experimentally. Reason: Directly demonstrated p38-cascade activation (multiple IDA); a core biological process. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt leading to activation of the JNK and MAP kinase p38
GO:0042733 embryonic digit morphogenesis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic annotation of embryonic digit morphogenesis, corroborated by the human disease phenotype (split-foot malformation) and IMP evidence. Reason: Supported by the SFMMP disease phenotype and IMP evidence, but a developmental outcome downstream of MAP3K20's core kinase/stress-signaling function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Split-foot malformation with mesoaxial polydactyly
GO:0051403 stress-activated MAPK cascade	IEA GO_REF:0000120	ACCEPT	Summary: MAP3K20 is a stress-activated component driving the JNK/p38 (stress-activated MAPK) cascade; a core biological process. Reason: Strongly supported by experimental evidence (ribotoxic stress, osmotic shock, ionizing radiation); core process. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Stress-activated component of a protein kinase signal
GO:0060173 limb development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog/IMP-supported role in limb development, consistent with the split-foot malformation phenotype. A developmental outcome. Reason: Supported by disease genetics but downstream of MAP3K20's core kinase function; non-core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Split-foot malformation with mesoaxial polydactyly
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence (HPA) cytosolic localization, consistent with the predominant compartment and ribosome-associated function. Reason: IDA-supported cytosolic localization agrees with the documented site of action. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Cytoplasm, cytosol
GO:0005634 nucleus	EXP PMID:15684425 Phosphorylation of Ser28 in histone H3 mediated by mixed lin...	KEEP AS NON CORE	Summary: Experimental nuclear localization, associated with MAP3K20 histone H3 Ser-28 kinase activity. A secondary localization. Reason: Experimentally documented nuclear pool (histone-kinase context) but secondary to the predominant cytoplasmic localization. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt histone kinase by phosphorylating histone H3
GO:0005737 cytoplasm	EXP PMID:15684425 Phosphorylation of Ser28 in histone H3 mediated by mixed lin...	ACCEPT	Summary: Experimental cytoplasmic localization, the predominant compartment. Reason: Direct experimental support for cytoplasmic localization. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0106310 protein serine kinase activity	EXP PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Experimentally demonstrated serine kinase activity (original MRK/ZAK characterization). Reason: Direct experimental support for the core catalytic function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0106310 protein serine kinase activity	EXP PMID:14521931 Effect of C-terminal truncations on MLK7 catalytic activity ...	ACCEPT	Summary: Experimentally demonstrated serine kinase activity. Reason: Direct experimental support for the core catalytic function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0106310 protein serine kinase activity	EXP PMID:26999302 Structure of the Human Protein Kinase ZAK in Complex with Ve...	ACCEPT	Summary: Experimentally demonstrated serine kinase activity. Reason: Direct experimental support for the core catalytic function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0106310 protein serine kinase activity	EXP PMID:32289254 ZAKα Recognizes Stalled Ribosomes through Partially Redundan...	ACCEPT	Summary: Experimentally demonstrated serine kinase activity (ZAKalpha ribotoxic stress study). Reason: Direct experimental support for the core catalytic function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0106310 protein serine kinase activity	EXP PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: Experimentally demonstrated serine kinase activity (ribosome-collision cell-fate study). Reason: Direct experimental support for the core catalytic function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0106310 protein serine kinase activity	EXP PMID:35857590 ZAKα-driven ribotoxic stress response activates the human NL...	ACCEPT	Summary: Experimentally demonstrated serine kinase activity (NLRP1 inflammasome study). Reason: Direct experimental support for the core catalytic function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0000165 MAPK cascade	IDA PMID:18331592 ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-ind...	ACCEPT	Summary: MAP3K20 functions in the MAPK cascade; supported by direct evidence. Reason: Directly demonstrated involvement in MAPK signaling; consistent with the core role, though the specific JNK/p38 cascade terms are more precise. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0006954 inflammatory response	IMP PMID:18331592 ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-ind...	KEEP AS NON CORE	Summary: MAP3K20 contributes to inflammatory signaling (consistent with its later-established role in the NLRP1 inflammasome/pyroptosis). Reason: A genuine downstream outcome of MAP3K20 stress signaling, but broad; the specific pyroptotic/NLRP1 role is captured by other terms. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt leading to activation of the NLRP1 inflammasome and subsequent
GO:0051403 stress-activated MAPK cascade	IDA PMID:20559024 ZAK is required for doxorubicin, a novel ribotoxic stressor,...	ACCEPT	Summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade; a core process. Reason: Directly demonstrated stress-activated MAPK signaling. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Stress-activated component of a protein kinase signal
GO:0004706 JUN kinase kinase kinase activity	IDA PMID:14521931 Effect of C-terminal truncations on MLK7 catalytic activity ...	ACCEPT	Summary: MAP3K20 acts as a JNK kinase kinase (phosphorylating MKK4/MKK7 upstream of JNK); a specific, core molecular function. Reason: Directly demonstrated JNKKK activity; a precise, core MF. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:15737997 Complete inhibition of anisomycin and UV radiation but not c...	ACCEPT	Summary: Direct evidence for MAP kinase kinase kinase activity; a core molecular function. Reason: Directly demonstrated MAP3K activity. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0007254 JNK cascade	IDA PMID:14521931 Effect of C-terminal truncations on MLK7 catalytic activity ...	ACCEPT	Summary: Direct evidence for MAP3K20 activation of the JNK cascade; a core process. Reason: Directly demonstrated JNK-cascade involvement. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0007254 JNK cascade	IDA PMID:15737997 Complete inhibition of anisomycin and UV radiation but not c...	ACCEPT	Summary: Direct evidence for MAP3K20 activation of the JNK cascade. Reason: Directly demonstrated JNK-cascade involvement. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0038066 p38MAPK cascade	IDA PMID:15737997 Complete inhibition of anisomycin and UV radiation but not c...	ACCEPT	Summary: Direct evidence for MAP3K20 activation of the p38 cascade. Reason: Directly demonstrated p38-cascade involvement. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt leading to activation of the JNK and MAP kinase p38
GO:0004674 protein serine/threonine kinase activity	IDA PMID:35857590 ZAKα-driven ribotoxic stress response activates the human NL...	ACCEPT	Summary: Direct evidence for serine/threonine kinase activity (NLRP1 study); core molecular function. Reason: Directly demonstrated kinase activity. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0004706 JUN kinase kinase kinase activity	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: Direct evidence for JNKKK activity in the ribosome-collision cell-fate study. Reason: Directly demonstrated JNKKK activity; core MF. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:32289254 ZAKα Recognizes Stalled Ribosomes through Partially Redundan...	ACCEPT	Summary: Direct evidence for MAP3K activity in the ZAKalpha ribotoxic stress study. Reason: Directly demonstrated MAP3K activity; core MF. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: Direct evidence for MAP3K activity in the ribosome-collision cell-fate study. Reason: Directly demonstrated MAP3K activity; core MF. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:35857590 ZAKα-driven ribotoxic stress response activates the human NL...	ACCEPT	Summary: Direct evidence for MAP3K activity in the NLRP1 inflammasome study. Reason: Directly demonstrated MAP3K activity; core MF. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0007254 JNK cascade	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: Direct evidence for JNK-cascade activation upon ribosome collisions. Reason: Directly demonstrated JNK-cascade involvement in ribotoxic stress. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0030295 protein kinase activator activity	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: MAP3K20 activates EIF2AK4/GCN2 independently of its own kinase activity, acting as a protein kinase activator in the integrated stress response branch. Reason: Directly demonstrated; MAP3K20 activates GCN2 kinase-independently, a genuine and distinctive molecular function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt MAP3K20 activates EIF2AK4/GCN2
GO:0031098 stress-activated protein kinase signaling cascade	IDA PMID:35857590 ZAKα-driven ribotoxic stress response activates the human NL...	ACCEPT	Summary: Direct evidence for MAP3K20 in stress-activated protein kinase signaling (NLRP1/ribotoxic stress); a core process. Reason: Directly demonstrated stress-activated signaling. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Stress-activated component of a protein kinase signal
GO:0038066 p38MAPK cascade	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: Direct evidence for p38-cascade activation upon ribosome collisions. Reason: Directly demonstrated p38-cascade involvement in ribotoxic stress. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt leading to activation of the JNK and MAP kinase p38
GO:0038066 p38MAPK cascade	IDA PMID:35857590 ZAKα-driven ribotoxic stress response activates the human NL...	ACCEPT	Summary: Direct evidence for p38-cascade activation in the NLRP1/ribotoxic stress study. Reason: Directly demonstrated p38-cascade involvement. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt leading to activation of the JNK and MAP kinase p38
GO:0043022 ribosome binding	IDA PMID:32289254 ZAKα Recognizes Stalled Ribosomes through Partially Redundan...	ACCEPT	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. Reason: Directly demonstrated ribosome binding underlying the ribotoxic-stress sensor role; core MF for ZAKalpha. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt directly binds to the ribosome by inserting its
GO:0043022 ribosome binding	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: ZAKalpha binds the ribosome and preferentially associates with colliding ribosomes; core sensor function. Reason: Directly demonstrated ribosome binding; core MF for the sensor role. Supporting Evidence: PMID:32610081 ZAKα preferentially associates with colliding ribosomes relative to monosomes.
GO:0043068 positive regulation of programmed cell death	IDA PMID:32289254 ZAKα Recognizes Stalled Ribosomes through Partially Redundan...	ACCEPT	Summary: MAP3K20 acts upstream of programmed cell death triggered by dangerous levels of ribosome collisions (via JNK/p38). Reason: Directly demonstrated; MAP3K20 promotes programmed cell death in response to ribotoxic stress. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt pathways that promote programmed cell death
GO:0043068 positive regulation of programmed cell death	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: MAP3K20 acts upstream of programmed cell death in the ribosome-collision cell-fate decision. Reason: Directly demonstrated cell-death-promoting role downstream of ribosome collisions. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt pathways that promote programmed cell death
GO:0046777 protein autophosphorylation	IDA PMID:32289254 ZAKα Recognizes Stalled Ribosomes through Partially Redundan...	ACCEPT	Summary: Ribosome collisions trigger MAP3K20 autophosphorylation and activation; directly demonstrated. Reason: Directly demonstrated autophosphorylation, the activation step of the sensor. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt trigger the autophosphorylation and activation of
GO:0051403 stress-activated MAPK cascade	IDA PMID:32289254 ZAKα Recognizes Stalled Ribosomes through Partially Redundan...	ACCEPT	Summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade (ribotoxic stress); a core process. Reason: Directly demonstrated stress-activated MAPK signaling in the ribotoxic stress response. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Stress-activated component of a protein kinase signal
GO:0051403 stress-activated MAPK cascade	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade (ribosome-collision study). Reason: Directly demonstrated stress-activated MAPK signaling. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Stress-activated component of a protein kinase signal
GO:0070181 small ribosomal subunit rRNA binding	IDA PMID:32289254 ZAKα Recognizes Stalled Ribosomes through Partially Redundan...	ACCEPT	Summary: ZAKalpha binds helix 14 of 18S rRNA in the small ribosomal subunit, the molecular basis of its ribosome-collision sensing. Reason: Directly demonstrated 18S rRNA binding (helix 14); a precise, mechanistically important molecular function for the sensor. Supporting Evidence: PMID:32289254 ZAKα binds helix 14 of 18S ribosomal RNA (rRNA).
GO:0070269 pyroptotic inflammatory response	IDA PMID:35857590 ZAKα-driven ribotoxic stress response activates the human NL...	ACCEPT	Summary: ZAKalpha drives UV-B-induced pyroptosis by activating the NLRP1 inflammasome (directly phosphorylating NLRP1). Reason: Directly demonstrated; MAP3K20 acts upstream of NLRP1-driven pyroptosis. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt leading to activation of the NLRP1 inflammasome and subsequent
GO:0071493 cellular response to UV-B	IDA PMID:35857590 ZAKα-driven ribotoxic stress response activates the human NL...	ACCEPT	Summary: ZAKalpha mediates the cellular response to UV-B (ribosome collisions activate MAP3K20, which phosphorylates NLRP1). Reason: Directly demonstrated UV-B-triggered MAP3K20 signaling; a genuine process. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt triggering the NLRP1 inflammasome in response to UV-B
GO:0140469 GCN2-mediated signaling	IDA PMID:32610081 Ribosome Collisions Trigger General Stress Responses to Regu...	ACCEPT	Summary: MAP3K20 acts upstream of GCN2-mediated signaling, activating EIF2AK4/GCN2 (kinase-independently) to engage the integrated stress response. Reason: Directly demonstrated; a distinctive role of MAP3K20 in routing ribosome-collision signals to the ISR via GCN2. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt MAP3K20 activates EIF2AK4/GCN2
GO:0004706 JUN kinase kinase kinase activity	IDA PMID:12220515 Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to acti...	ACCEPT	Summary: Direct evidence for JNKKK activity; a precise, core molecular function. Reason: Directly demonstrated JNKKK activity. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0007254 JNK cascade	IDA PMID:12220515 Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to acti...	ACCEPT	Summary: Direct evidence for MAP3K20 in the JNK cascade. Reason: Directly demonstrated JNK-cascade involvement. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0046777 protein autophosphorylation	IDA PMID:12220515 Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to acti...	ACCEPT	Summary: Direct evidence for MAP3K20 autophosphorylation, its activation mechanism. Reason: Directly demonstrated autophosphorylation. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt trigger the autophosphorylation and activation of
GO:0004706 JUN kinase kinase kinase activity	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Direct evidence for JNKKK activity (original MRK/ZAK characterization). Reason: Directly demonstrated JNKKK activity. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0007254 JNK cascade	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Direct evidence for MAP3K20 in the JNK cascade. Reason: Directly demonstrated JNK-cascade involvement. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Activates JNK through
GO:0038066 p38MAPK cascade	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Direct evidence for MAP3K20 in the p38 cascade. Reason: Directly demonstrated p38-cascade involvement. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt leading to activation of the JNK and MAP kinase p38
GO:1904291 positive regulation of mitotic DNA damage checkpoint	IDA PMID:15342622 The stress kinase MRK contributes to regulation of DNA damag...	KEEP AS NON CORE	Summary: MAP3K20 may regulate the S/G2 DNA-damage checkpoint via phosphorylation of CHEK2; a context-specific role. Reason: Experimentally reported checkpoint role (CHEK2 phosphorylation) but distinct from MAP3K20's predominant stress-activated MAPK/ribotoxic-stress function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt regulation of S and G2 cell cycle
GO:0051403 stress-activated MAPK cascade	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Direct evidence for MAP3K20 in the stress-activated MAPK cascade. Reason: Directly demonstrated stress-activated MAPK signaling; core process. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Stress-activated component of a protein kinase signal
GO:0071480 cellular response to gamma radiation	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	KEEP AS NON CORE	Summary: MAP3K20 (MRK) mediates a response to gamma/ionizing radiation, consistent with its stress-activated role. Reason: A genuine stress-response context but one of several stress stimuli; the ribotoxic stress / stress-activated MAPK cascade is the core. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt osmotic shock and ionizing
GO:0042733 embryonic digit morphogenesis	IMP PMID:26755636 Exome sequencing and CRISPR/Cas genome editing identify muta...	KEEP AS NON CORE	Summary: Loss-of-function variants cause split-foot malformation, implicating MAP3K20 in embryonic digit morphogenesis. Reason: Supported by human disease genetics (SFMMP) but a developmental outcome downstream of the core kinase function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Split-foot malformation with mesoaxial polydactyly
GO:0060173 limb development	IMP PMID:26755636 Exome sequencing and CRISPR/Cas genome editing identify muta...	KEEP AS NON CORE	Summary: Loss-of-function variants cause limb/foot malformation, implicating MAP3K20 in limb development. Reason: Supported by disease genetics but downstream of the core kinase function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Split-foot malformation with mesoaxial polydactyly
GO:0003723 RNA binding	HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt directly binds to the ribosome by inserting its
GO:0000077 DNA damage checkpoint signaling	IMP PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	KEEP AS NON CORE	Summary: MAP3K20 (MRK) was implicated in DNA-damage checkpoint signaling after gamma irradiation; a context-specific role. Reason: Reported checkpoint role, but distinct from and secondary to MAP3K20's predominant ribotoxic-stress / stress-activated MAPK function. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt regulation of S and G2 cell cycle
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Direct evidence for MAP3K activity (original MRK/ZAK characterization); core molecular function. Reason: Directly demonstrated MAP3K activity. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0008219 cell death	NAS PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	KEEP AS NON CORE	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. Reason: Correct in spirit but a broad term; the specific programmed-cell-death terms capture the role. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt promotes programmed cell death
GO:0030154 cell differentiation	NAS PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	MARK AS OVER ANNOTATED	Summary: Broad cell-differentiation annotation (non-author statement) with no specific MAP3K20 mechanism documented. Reason: Very general NAS annotation not supported by specific MAP3K20 evidence; its documented roles are stress-activated signaling and ribotoxic stress sensing. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Stress-activated component of a protein kinase signal
GO:0000287 magnesium ion binding	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Direct evidence for magnesium binding by the kinase domain. Reason: Standard catalytic cofactor binding, experimentally supported. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0005524 ATP binding	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: Direct evidence for ATP binding by the kinase domain. Reason: Standard catalytic cofactor binding, experimentally supported. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt ATP binding
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity-based cytoplasmic localization, consistent with the predominant compartment. Reason: Agrees with experimental cytoplasm/cytosol localization. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0006468 protein phosphorylation	IDA PMID:11836244 MRK, a mixed lineage kinase-related molecule that plays a ro...	ACCEPT	Summary: MAP3K20 phosphorylates substrate proteins; protein phosphorylation is the direct process outcome of its kinase activity. Reason: Directly supported process annotation for a protein kinase. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt Acts by catalyzing phosphorylation of MAP kinase
GO:0043065 positive regulation of apoptotic process	IDA PMID:10924358 Cloning and expression of ZAK, a mixed lineage kinase-like p...	ACCEPT	Summary: MAP3K20 positively regulates apoptosis in response to stress, consistent with its programmed-cell-death-promoting role. Reason: Directly demonstrated pro-apoptotic role downstream of MAP3K20 stress signaling. Supporting Evidence: file:human/MAP3K20/MAP3K20-uniprot.txt promotes programmed cell death

Core Functions

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:

MAP kinase kinase kinase activity

Cellular Locations:

cytosol

Supporting Evidence:

file:human/MAP3K20/MAP3K20-uniprot.txt
Acts by catalyzing phosphorylation of MAP kinase
file:human/MAP3K20/MAP3K20-uniprot.txt
leading to activation of the JNK and MAP kinase p38

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:

ribosome binding

Cellular Locations:

cytosol

Supporting Evidence:

file:human/MAP3K20/MAP3K20-uniprot.txt
directly binds to the ribosome by inserting its
PMID:32289254
ZAKα binds helix 14 of 18S ribosomal RNA (rRNA).

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:

protein serine/threonine kinase activity

Cellular Locations:

cytosol

Supporting Evidence:

file:human/MAP3K20/MAP3K20-uniprot.txt
triggering the NLRP1 inflammasome in response to UV-B
file:human/MAP3K20/MAP3K20-uniprot.txt
pathways that promote programmed cell death

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000116

Gene Ontology annotation based on rule-based mapping of RHEA reactions to GO molecular functions

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10924358

Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif.

PMID:11836244

MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest.

MRK/ZAK (MAP3K20) is a serine/threonine MAP3K that activates JNK and p38 and functions in gamma-radiation-induced cell-cycle arrest/checkpoint signaling.

PMID:12220515

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.

PMID:14521931

Effect of C-terminal truncations on MLK7 catalytic activity and JNK activation.

PMID:15342622

The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway.

PMID:15684425

Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase alpha.

PMID:15737997

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.

PMID:15778465

Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:18331592

ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-induced proinflammatory cytokine expression.

PMID:20559024

ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

PMID:26755636

Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

Loss-of-function MAP3K20/ZAK variants cause split-foot malformation with mesoaxial polydactyly, implicating MAP3K20 in limb/digit development.

PMID:26999302

Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32289254

ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains.

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.

PMID:32610081

Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate.

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.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:35857590

ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome.

ZAKalpha-driven ribotoxic stress response (e.g. UV-B) activates the human NLRP1 inflammasome via direct NLRP1 phosphorylation, leading to pyroptosis.

PMID:36931259

A central chaperone-like role for 14-3-3 proteins in human cells.

Suggested Experiments

Experiment: 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.

Experiment: 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.

Experiment: Patient-derived myotubes carrying CNM6 variants assayed for ribotoxic stress signaling and proteostasis to test whether impaired ZAKalpha surveillance contributes to the myopathy.

📚 Additional Documentation

Notes

(MAP3K20-notes.md)

MAP3K20 (Q9NYL2) research notes

Summary

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).

Core functions (from review)

GO:0004709 MAP kinase kinase kinase activity — 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.
GO:0043022 ribosome binding — 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.
GO:0004674 protein serine/threonine kinase activity — 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.

Provenance

Research and verbatim supporting quotes are recorded inline in MAP3K20-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(MAP3K20-pn-notes.md)

MAP3K20 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9NYL2
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07c
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/MAP3K20/MAP3K20-ai-review.yaml
AIGR review HTML: present - genes/human/MAP3K20/MAP3K20-ai-review.html
Gene notes: present - genes/human/MAP3K20/MAP3K20-notes.md
GOA TSV: present - genes/human/MAP3K20/MAP3K20-goa.tsv
UniProt record: present - genes/human/MAP3K20/MAP3K20-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/MAP3K20.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/MAP3K20.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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).
Existing/core annotation action counts: ACCEPT: 61; KEEP_AS_NON_CORE: 21; MARK_AS_OVER_ANNOTATED: 4

PN Consistency Summary

Consistency: Consistent. Deep research, review, and PN agree MAP3K20/ZAKalpha is the ribotoxic-stress-response kinase — the proximal sensor of ribosome collisions (binds ribosome / helix 14 of 18S rRNA, autophosphorylates) that routes signals to JNK/p38 (cell death) or GCN2 (ISR). PN deliberately places it in "other RQC processes" with type=no_mapping (sensor/signaling, not a core ubiquitination/rescue effector), which matches the review framing exactly. No contradiction.
PN story / NEW pressure: Subtle. PN maps only the GROUP node GO:0006515 (protein quality control) — broad. MAP3K20 is a ribotoxic-stress SENSOR/SIGNALING kinase, not a protein-QC catabolic effector, so GO:0006515 over-attributes a QC-disposal process to it. The review's rich, accurate captures are GO:0043022 ribosome binding (IDA), GO:0070181 small ribosomal subunit rRNA binding (IDA), GO:0051403 stress-activated MAPK cascade, GO:0140469 GCN2-mediated signaling, GO:0070269 pyroptosis. There is no missing term — the ribotoxic-stress/collision-sensing role is well annotated. Conclusion: already captured; PN group GO:0006515 over-reaches for a sensor kinase.
Evidence alignment: PN lists no reference titles. Review anchors on PMID:32289254 (ZAKalpha sensor domains / 18S helix-14), PMID:32610081 (collisions → cell fate, p38/JNK vs GCN2), PMID:35857590 (NLRP1 inflammasome/pyroptosis), plus the classical MRK/ZAK kinase papers. No citation conflict; PN carries no PMIDs.
Verdict: Consistent; ribotoxic-stress sensor role already well captured — PN group GO:0006515 over-reaches for a signaling kinase. Recommended edits: treat group-node GO:0006515 as context-only for MAP3K20 (do not propagate the protein-QC catabolic process to a sensor/signaling kinase) [MAP]; no YAML changes needed.

Full Consistency Review

UniProt: Q9NYL2 (ZAK/MLK7/MRK) · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
PN placement: Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes ; PN-node mapping: type other RQC processes=no_mapping; group Ribosome-associated QC=mapped→GO:0006515 protein quality control (new_to_goa); class/branch=context_only.
Consistency: Consistent. Deep research, review, and PN agree MAP3K20/ZAKalpha is the ribotoxic-stress-response kinase — the proximal sensor of ribosome collisions (binds ribosome / helix 14 of 18S rRNA, autophosphorylates) that routes signals to JNK/p38 (cell death) or GCN2 (ISR). PN deliberately places it in "other RQC processes" with type=no_mapping (sensor/signaling, not a core ubiquitination/rescue effector), which matches the review framing exactly. No contradiction.
PN story / NEW pressure: Subtle. PN maps only the GROUP node GO:0006515 (protein quality control) — broad. MAP3K20 is a ribotoxic-stress SENSOR/SIGNALING kinase, not a protein-QC catabolic effector, so GO:0006515 over-attributes a QC-disposal process to it. The review's rich, accurate captures are GO:0043022 ribosome binding (IDA), GO:0070181 small ribosomal subunit rRNA binding (IDA), GO:0051403 stress-activated MAPK cascade, GO:0140469 GCN2-mediated signaling, GO:0070269 pyroptosis. There is no missing term — the ribotoxic-stress/collision-sensing role is well annotated. Conclusion: already captured; PN group GO:0006515 over-reaches for a sensor kinase.
Mapping strategy: Correct that the type node ("other RQC processes") is no_mapping. The group-level GO:0006515 should be treated as context_only for MAP3K20 — it is a heterogeneous QC umbrella and MAP3K20's role is upstream sensing/signaling, not nascent-chain disposal. Distinguishing broad GO:0006515 from MAP3K20's specific ribosome-binding/stress-cascade terms is exactly the branch-guidance concern.
Evidence alignment: PN lists no reference titles. Review anchors on PMID:32289254 (ZAKalpha sensor domains / 18S helix-14), PMID:32610081 (collisions → cell fate, p38/JNK vs GCN2), PMID:35857590 (NLRP1 inflammasome/pyroptosis), plus the classical MRK/ZAK kinase papers. No citation conflict; PN carries no PMIDs.
Verdict: Consistent; ribotoxic-stress sensor role already well captured — PN group GO:0006515 over-reaches for a signaling kinase. Recommended edits: treat group-node GO:0006515 as context-only for MAP3K20 (do not propagate the protein-QC catabolic process to a sensor/signaling kinase) [MAP]; no YAML changes needed.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07c
review_yaml: genes/human/MAP3K20/MAP3K20-ai-review.yaml
PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | other RQC processes

UniProt: Q9NYL2
In branches: TR
PN-node mapping records (path + ancestors):
- [type] Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [group] Translation|Cytosolic translation|Ribosome-associated QC
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
  rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
- [class] Translation|Cytosolic translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
  rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
  rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

Projected GO annotations (1)

GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

MAP3K20

Gene Description

Existing Annotations Review

Core Functions

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

MAP3K20 (Q9NYL2) research notes

Summary

Core functions (from review)

Provenance

Pn Notes

MAP3K20 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | other RQC processes

Projected GO annotations (1)

Note

📄 View Raw YAML