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).
| 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 ZAKΞ± 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 ZAKΞ±-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 ZAKΞ±-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 ZAKΞ± 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 ZAKΞ±-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 ZAKΞ±-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 ZAKΞ±-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 ZAKΞ± 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 ZAKΞ± preferentially associates with colliding ribosomes relative to monosomes. |
| GO:0043068 positive regulation of programmed cell death | IDA PMID:32289254 ZAKΞ± 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 ZAKΞ± 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 ZAKΞ± 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 ZAKΞ± 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 ZAKΞ± binds helix 14 of 18S ribosomal RNA (rRNA). |
| GO:0070269 pyroptotic inflammatory response | IDA PMID:35857590 ZAKΞ±-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 ZAKΞ±-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 |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: 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)?
Q: How do the centronuclear myopathy (CNM6) and split-foot malformation (SFMMP) phenotypes relate mechanistically to defects in ribotoxic stress sensing versus other MAP3K20 functions?
Q: Does the kinase-independent activation of GCN2 by MAP3K20 reflect a scaffolding interaction, and what is its structural basis?
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.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)