MAD2L1 (Mitotic Arrest Deficient 2-Like 1) encodes a HORMA domain-containing protein that is a core effector of the spindle assembly checkpoint (SAC). MAD2 exists in two interconvertible conformations: an open form (O-MAD2) that predominates in the cytosol and a closed form (C-MAD2) that binds its key targets. At unattached kinetochores during prometaphase, MAD1:C-MAD2 core complexes recruit cytosolic O-MAD2 and catalyze its conversion to C-MAD2, enabling binding to CDC20. The resulting CDC20:MAD2 complex associates with BUB3 and BUBR1 to form the mitotic checkpoint complex (MCC), which inhibits the anaphase-promoting complex/cyclosome (APC/C-CDC20), thereby preventing premature anaphase until all chromosomes achieve proper bipolar attachment. Checkpoint silencing is mediated by p31comet (MAD2L1BP) and the AAA+ ATPase TRIP13, which remodel C-MAD2 back to O-MAD2 and disassemble the MCC. MAD2 also localizes to the nuclear pore complex via TPR during interphase, potentially facilitating early MCC assembly.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000776 kinetochore | IBA GO_REF:0000033 | ACCEPT | Summary: MAD2 localization to kinetochores is well-established and central to its checkpoint function. The original discovery paper (PMID:8824189) showed MAD2 localizes to kinetochores after chromosome condensation but is absent from kinetochores at metaphase. Reason: Kinetochore localization is a core aspect of MAD2 function. IBA inference from phylogenetic analysis is consistent with abundant experimental evidence showing MAD2 recruitment to unattached kinetochores via the MAD1:MAD2 core complex. Supporting Evidence: PMID:8824189 Human, or Homo sapiens, MAD2 (hsMAD2) was localized at the kinetochore after chromosome condensation but was no longer observed at the kinetochore in metaphase, suggesting that MAD2 might monitor the completeness of the spindle-kinetochore attachment PMID:18981471 Depletion of Tpr decreases the levels of Mad1 at kinetochores during prometaphase, correlating with the inability of Mad1 to activate Mad2 file:human/MAD2L1/MAD2L1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0007094 mitotic spindle assembly checkpoint signaling | IBA GO_REF:0000033 | ACCEPT | Summary: MAD2 is a core component of the spindle assembly checkpoint. The deep research confirms that MAD2 is "a core effector of the spindle assembly checkpoint (SAC)" and is essential for MCC formation and APC/C inhibition. Reason: This is the primary biological process for MAD2. The IBA annotation is fully consistent with decades of research establishing MAD2 as essential for SAC signaling. Supporting Evidence: PMID:8824189 The human homolog of MAD2 was isolated and shown to be a necessary component of the mitotic checkpoint in HeLa cells by antibody electroporation experiments PMID:18981471 The mitotic arrest-deficient protein Mad1 forms a complex with Mad2, which is required for imposing mitotic arrest on cells in which the spindle assembly is perturbed |
| GO:0000776 kinetochore | IEA GO_REF:0000120 | ACCEPT | Summary: Computational annotation to kinetochore based on combined automated methods. Duplicates the IBA annotation above. Reason: Consistent with the IBA annotation and extensive experimental evidence. Redundant annotations with different evidence types are acceptable. Supporting Evidence: PMID:8824189 Human, or Homo sapiens, MAD2 (hsMAD2) was localized at the kinetochore after chromosome condensation but was no longer observed at the kinetochore in metaphase |
| GO:0000922 spindle pole | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt subcellular location annotation indicates spindle pole localization. The deep research mentions MAD2 presence at spindle poles as part of mitotic checkpoint dynamics. Reason: Spindle pole localization is documented in UniProt and consistent with MAD2's role in mitotic checkpoint function. This represents a secondary localization site during mitosis. Supporting Evidence: PMID:20133940 Here, we show association of another nucleoporin, termed Tpr (translocated promoter region), with the molecular motors dynein and dynactin, which both orchestrate with the spindle checkpoints Mad1 and Mad2 during cell division |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization is inferred from automated methods. UniProt confirms nuclear localization through IDA evidence. Reason: Nuclear localization is experimentally validated (see IDA annotations below). MAD2 is recruited to the nuclear pore complex by TPR during interphase. Supporting Evidence: PMID:18981471 Tpr directly binds to Mad1 and Mad2...Depletion of Tpr in HeLa cells disrupts the NPC localization of Mad1 and Mad2 during interphase |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic localization is inferred from automated methods. The open form of MAD2 (O-MAD2) exists as a cytosolic pool that is recruited to kinetochores. Reason: The cytosolic O-MAD2 pool is essential for the template model of MAD2 activation. Cytoplasmic localization is well-documented. Supporting Evidence: PMID:19010891 MAD1beta localized in the cytoplasm...MAD1beta was found to physically interact with MAD2 and sequester it in the cytoplasm |
| GO:0051301 cell division | IEA GO_REF:0000043 | ACCEPT | Summary: Inferred from UniProt keyword "Cell division". MAD2 function in the spindle checkpoint is essential for proper cell division. Reason: This is a broader process that encompasses the SAC. MAD2's role in preventing premature anaphase is essential for accurate chromosome segregation during cell division. Supporting Evidence: PMID:8824189 In Saccharomyces cerevisiae, MAD2 is required for mitotic arrest if the spindle assembly is perturbed |
| GO:0051783 regulation of nuclear division | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine learning annotation for regulation of nuclear division. MAD2 regulates nuclear division by controlling the metaphase-to-anaphase transition. Reason: This is an appropriate parent term for MAD2's role in checkpoint signaling. MAD2-mediated MCC formation regulates the timing of anaphase onset. Supporting Evidence: PMID:10700282 The checkpoint protein Mad2 inhibits the activity of the anaphase promoting complex by sequestering Cdc20 until all chromosomes are aligned at the metaphase plate |
| GO:1901991 negative regulation of mitotic cell cycle phase transition | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA annotation for negative regulation of mitotic cell cycle phase transition. MAD2 inhibits the metaphase-to-anaphase transition via APC/C inhibition. Reason: Accurate annotation. MAD2 negatively regulates the metaphase-to-anaphase transition by inhibiting APC/C-CDC20 activity through MCC formation. Supporting Evidence: PMID:10700282 The checkpoint protein Mad2 inhibits the activity of the anaphase promoting complex by sequestering Cdc20 |
| GO:1990728 mitotic spindle assembly checkpoint MAD1-MAD2 complex | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA annotation for membership in the MAD1-MAD2 complex. This is a core structural complex essential for MAD2 activation and checkpoint signaling. Reason: Highly accurate annotation. The MAD1:C-MAD2 core complex at kinetochores is essential for templated conversion of O-MAD2 to C-MAD2 and subsequent CDC20 capture. Supporting Evidence: PMID:12006501 The crystal structure of the Mad1-Mad2 complex reveals an asymmetric tetramer, with elongated Mad1 monomers parting from a coiled-coil to form two connected sub-complexes with Mad2 PMID:18981471 The mitotic arrest-deficient protein Mad1 forms a complex with Mad2 |
| GO:0005515 protein binding | IPI PMID:10527948 Evidence for an interaction of the metalloprotease-disintegr... | MARK AS OVER ANNOTATED | Summary: Interaction with ADAM17/TACE demonstrated by immunoprecipitation. This is an unusual interaction partner for a checkpoint protein. Reason: While the interaction is documented, "protein binding" is too vague. The interaction with ADAM17 is not clearly related to MAD2's core checkpoint function and may represent a peripheral or indirect interaction. Supporting Evidence: PMID:10527948 Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2) |
| GO:0005515 protein binding | IPI PMID:15182668 Spindle checkpoint protein dynamics at kinetochores in livin... | MODIFY | Summary: Interaction with CDC20 (Q12834) documented. This is a core functional interaction for checkpoint signaling. Reason: The interaction with CDC20 is the primary functional output of MAD2 activation. "Protein binding" is too vague; this should be annotated to the specific complex or with a more informative term. Proposed replacements: mitotic checkpoint complex, CDC20-MAD2 subcomplex Supporting Evidence: PMID:10700282 Mad2 possesses a novel three-layered alpha/beta fold with three alpha-helices packed between two beta-sheets...Mad2 and Cdc20 form a tight 1:1 heterodimeric complex |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: High-throughput protein interaction study. Interactions with TSC22D4 and MAD1L1 documented. MAD1L1 interaction is core; TSC22D4 significance unclear. Reason: Generic protein binding annotation from HTP study. The MAD1L1 interaction is captured in more specific annotations. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network |
| GO:0005515 protein binding | IPI PMID:16525508 Determinants of conformational dimerization of Mad2 and its ... | MODIFY | Summary: Interaction with CDC20 documented in study of MAD2 conformational dimerization. Reason: This study specifically addresses MAD2-CDC20 interaction in the context of conformational dimerization and p31comet inhibition. Should be annotated to more specific complex terms. Proposed replacements: mitotic checkpoint complex, CDC20-MAD2 subcomplex Supporting Evidence: PMID:16525508 Determinants of conformational dimerization of Mad2 and its inhibition by p31comet |
| GO:0005515 protein binding | IPI PMID:17443180 Anaphase initiation is regulated by antagonistic ubiquitinat... | MARK AS OVER ANNOTATED | Summary: Interactions with CDC27 (P30260) and CDC20 (Q12834) documented in study of ubiquitination/deubiquitination in anaphase initiation. Reason: Generic protein binding. CDC27 is an APC/C subunit; interaction likely reflects MCC-APC/C association. Core CDC20 interaction captured elsewhere. Supporting Evidence: PMID:17443180 Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities |
| GO:0005515 protein binding | IPI PMID:17443186 Ubiquitination by the anaphase-promoting complex drives spin... | MARK AS OVER ANNOTATED | Summary: Interactions with CDC27 and CDC20 documented in study of spindle checkpoint inactivation. Reason: Duplicate of interactions captured in more specific annotations. Generic protein binding is not informative. Supporting Evidence: PMID:17443186 Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation |
| GO:0005515 protein binding | IPI PMID:18022367 The Mad2 conformational dimer: structure and implications fo... | MODIFY | Summary: Interaction with CDC20 demonstrated in seminal structural study of the MAD2 conformational dimer. Reason: This landmark paper establishes the structural basis for O-MAD2/C-MAD2 dimerization and CDC20 binding. Should be annotated to specific complex terms. Proposed replacements: mitotic checkpoint complex, CDC20-MAD2 subcomplex Supporting Evidence: PMID:18022367 The structure of the O-Mad2-C-Mad2 conformational dimer is consistent with a catalytic model in which a C-Mad2 template facilitates the binding of O-Mad2 to Cdc20 |
| GO:0005515 protein binding | IPI PMID:18022368 p31comet blocks Mad2 activation through structural mimicry | MODIFY | Summary: Interaction with p31comet (MAD2L1BP, Q15013) demonstrated. p31comet is the key negative regulator of MAD2 that promotes checkpoint silencing. Reason: This is a functionally important interaction for checkpoint silencing. p31comet blocks MAD2 activation through structural mimicry. Should be annotated to a more specific MF term if available. Proposed replacements: identical protein binding Supporting Evidence: PMID:18022368 p31comet blocks Mad2 activation through structural mimicry |
| GO:0005515 protein binding | IPI PMID:18318601 Insights into mad2 regulation in the spindle checkpoint reve... | MARK AS OVER ANNOTATED | Summary: Interactions with CDC20 and MAD1L1 demonstrated in structural study of symmetric MAD2 dimer. Reason: Core interactions captured in more specific annotations. This study addresses homodimerization which is separately annotated. Supporting Evidence: PMID:18318601 Insights into mad2 regulation in the spindle checkpoint revealed by the crystal structure of the symmetric mad2 dimer |
| GO:0005515 protein binding | IPI PMID:18692475 A protein domain-based interactome network for C. elegans ea... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from C. elegans embryogenesis domain-based interactome. Reason: Generic protein binding from interactome study. MAD1-MAD2 interaction is well captured in more specific annotations. Supporting Evidence: PMID:18692475 A protein domain-based interactome network for C. elegans early embryogenesis |
| GO:0005515 protein binding | IPI PMID:19143472 The influence of catalysis on Mad2 activation dynamics | MARK AS OVER ANNOTATED | Summary: Interaction with CDC20 in study of Mad2 activation dynamics. Reason: Core CDC20 interaction captured elsewhere. Generic protein binding is not informative. Supporting Evidence: PMID:19143472 The influence of catalysis on mad2 activation dynamics |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | MARK AS OVER ANNOTATED | Summary: Interaction with KEAP1 from deubiquitinating enzyme interactome study. Reason: Interaction with KEAP1 is not clearly related to core checkpoint function. May represent an indirect or peripheral interaction. Supporting Evidence: PMID:19615732 Defining the human deubiquitinating enzyme interaction landscape |
| GO:0005515 protein binding | IPI PMID:20212161 ATP is required for the release of the anaphase-promoting co... | MARK AS OVER ANNOTATED | Summary: Interactions with BUB1B, CDC27, and CDC20 documented in study of ATP-dependent APC/C release from MCC inhibition. Reason: These interactions are core to MCC function but captured in more specific annotations. BUB1B (BUBR1) is an MCC component. Supporting Evidence: PMID:20212161 ATP is required for the release of the anaphase-promoting complex/cyclosome from inhibition by the mitotic checkpoint |
| GO:0005515 protein binding | IPI PMID:20360068 Systematic analysis of human protein complexes identifies ch... | MARK AS OVER ANNOTATED | Summary: Interaction with CDC20 from systematic analysis of chromosome segregation proteins. Reason: Core CDC20 interaction captured elsewhere. HTP study. Supporting Evidence: PMID:20360068 Systematic analysis of human protein complexes identifies chromosome segregation proteins |
| GO:0005515 protein binding | IPI PMID:20951947 Pharmacologic inhibition of the anaphase-promoting complex i... | MARK AS OVER ANNOTATED | Summary: Interaction with CDC27 from study of APC/C pharmacologic inhibition. Reason: CDC27 interaction reflects MCC-APC/C association. Captured in pathway annotations. Supporting Evidence: PMID:20951947 Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest |
| GO:0005515 protein binding | IPI PMID:21041666 Phosphorylation of the spindle checkpoint protein Mad2 regul... | MARK AS OVER ANNOTATED | Summary: Interactions with CDC20 and MAD1L1 documented in study of MAD2 phosphorylation and conformational transition. Reason: Core interactions captured elsewhere. Study addresses phosphoregulation of MAD2. Supporting Evidence: PMID:21041666 Phosphorylation of the spindle checkpoint protein Mad2 regulates its conformational transition |
| GO:0005515 protein binding | IPI PMID:21300909 p31comet promotes disassembly of the mitotic checkpoint comp... | MARK AS OVER ANNOTATED | Summary: Interactions with BUB1B, CDC27, and CDC20 in study of p31comet-mediated MCC disassembly. Reason: Core MCC interactions captured elsewhere. Supporting Evidence: PMID:21300909 p31comet Promotes disassembly of the mitotic checkpoint complex in an ATP-dependent process |
| GO:0005515 protein binding | IPI PMID:21407176 Evidence that Aurora B is implicated in spindle checkpoint s... | MARK AS OVER ANNOTATED | Summary: Interaction with CDC20 in study of Aurora B role in checkpoint signaling. Reason: Core CDC20 interaction captured elsewhere. Supporting Evidence: PMID:21407176 Evidence that Aurora B is implicated in spindle checkpoint signalling independently of error correction |
| GO:0005515 protein binding | IPI PMID:21666598 Shugoshin is a Mad1/Cdc20-like interactor of Mad2 | MARK AS OVER ANNOTATED | Summary: Interactions with p31comet and SGO2 documented. SGO2 as a MAD1/CDC20-like interactor. Reason: p31comet interaction captured elsewhere. SGO2 interaction may represent a regulatory mechanism but is not core to checkpoint function. Supporting Evidence: PMID:21666598 Shugoshin is a Mad1/Cdc20-like interactor of Mad2 |
| GO:0005515 protein binding | IPI PMID:21772247 Probing the in vivo function of Mad1:C-Mad2 in the spindle a... | MARK AS OVER ANNOTATED | Summary: Multiple interactions (BUB1B, CDC27, CDC20, p31comet, MAD1L1) from study probing Mad1:C-Mad2 function in vivo. Reason: Core interactions captured in specific annotations. HTP validation study. Supporting Evidence: PMID:21772247 Probing the in vivo function of Mad1:C-Mad2 in the spindle assembly checkpoint |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from liver protein interactome study. Reason: MAD1-MAD2 interaction captured in specific annotations. HTP study. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver |
| GO:0005515 protein binding | IPI PMID:22000412 Structure of a Blinkin-BUBR1 complex reveals an interaction ... | MARK AS OVER ANNOTATED | Summary: Interaction with BUB1B from structural study of Blinkin-BUBR1 complex. Reason: BUB1B/BUBR1 is an MCC component. Interaction captured in MCC annotations. Supporting Evidence: PMID:22000412 Structure of a Blinkin-BUBR1 complex reveals an interaction crucial for kinetochore-mitotic checkpoint regulation |
| GO:0005515 protein binding | IPI PMID:22340593 Aurora kinase-A inactivates DNA damage-induced apoptosis and... | MARK AS OVER ANNOTATED | Summary: Interaction with CDC20 from study of Aurora kinase-A and p73. Reason: Core CDC20 interaction captured elsewhere. Supporting Evidence: PMID:22340593 Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73 |
| GO:0005515 protein binding | IPI PMID:22493223 Structure of human Mad1 C-terminal domain reveals its involv... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from structural study of MAD1 C-terminal domain. Reason: MAD1-MAD2 interaction captured in specific annotations. Supporting Evidence: PMID:22493223 Structure of human Mad1 C-terminal domain reveals its involvement in kinetochore targeting |
| GO:0005515 protein binding | IPI PMID:24581499 Nuclear pores protect genome integrity by assembling a premi... | MARK AS OVER ANNOTATED | Summary: Interactions with CDC20 and MAD1L1 from study of nuclear pore-mediated anaphase inhibitor assembly. Reason: Core interactions captured elsewhere. Supporting Evidence: PMID:24581499 Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor |
| GO:0005515 protein binding | IPI PMID:25383541 The mitotic checkpoint complex binds a second CDC20 to inhib... | MARK AS OVER ANNOTATED | Summary: Interactions with BUB1B and CDC20 from study of MCC binding to second CDC20. Reason: Core MCC interactions captured elsewhere. Supporting Evidence: PMID:25383541 The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network | MARK AS OVER ANNOTATED | Summary: Multiple interactions (SDCBP, KEAP1, p31comet, TSC22D4) from proteome-scale interactome map. Reason: HTP interactome study. Core interactions captured elsewhere; peripheral interactions not clearly related to checkpoint function. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | MARK AS OVER ANNOTATED | Summary: Interaction with p31comet from disease mutation phenotyping study. Reason: p31comet interaction captured elsewhere. Supporting Evidence: PMID:25502805 A massively parallel pipeline to clone DNA variants and examine molecular phenotypes of human disease mutations |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | MARK AS OVER ANNOTATED | Summary: Interaction with BUB1B from kinase network analysis in TRAIL-induced apoptosis. Reason: BUB1B/BUBR1 interaction captured in MCC annotations. Supporting Evidence: PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy |
| GO:0005515 protein binding | IPI PMID:26258632 Mad1 promotes chromosome congression by anchoring a kinesin ... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from study of MAD1 role in chromosome congression. Reason: MAD1-MAD2 interaction captured in specific annotations. Supporting Evidence: PMID:26258632 Mad1 promotes chromosome congression by anchoring a kinesin motor to the kinetochore |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: Multiple interactions (CDC27, CDC20, p31comet, MAD1L1) from quantitative interactome study. Reason: Core interactions captured elsewhere. HTP study with stoichiometry data. Supporting Evidence: PMID:26496610 A human interactome in three quantitative dimensions organized by stoichiometries and abundances |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Interaction with TSC22D4 from disease network study. Reason: TSC22D4 interaction not clearly related to checkpoint function. HTP study. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from bioluminescence two-hybrid study. Reason: MAD1-MAD2 interaction captured in specific annotations. Supporting Evidence: PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from binary interactome mapping study. Reason: MAD1-MAD2 interaction captured in specific annotations. HTP study. Supporting Evidence: PMID:31467278 Maximizing binary interactome mapping with a minimal number of assays |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Interactions with KEAP1, p31comet, MAD1L1 from variant disruption study. Reason: Core interactions captured elsewhere. Study addresses variant effects on interactions. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome | MARK AS OVER ANNOTATED | Summary: Multiple interactions (DEPDC5, INSR, KEAP1, p31comet, EPM2AIP1, MAD1L1) from human binary interactome reference map. Reason: Core interactions captured elsewhere. Several peripheral interactions (DEPDC5, INSR, EPM2AIP1) not clearly related to checkpoint function. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from neurodegenerative disease interactome study. Reason: MAD1-MAD2 interaction captured in specific annotations. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Multiple interactions (BUB1B, INSR, CDC27, CDC20, p31comet, SGO2, EPM2AIP1, TSC22D4, MAD1L1) from cell-specific interactome study. Reason: Core interactions captured elsewhere. HTP dual proteome-scale study. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome |
| GO:0005515 protein binding | IPI PMID:35384245 Physical and functional interactome atlas of human receptor ... | MARK AS OVER ANNOTATED | Summary: Interaction with INSR (insulin receptor) from RTK interactome study. Reason: INSR interaction not clearly related to checkpoint function. May represent regulatory cross-talk or indirect interaction. Supporting Evidence: PMID:35384245 Physical and functional interactome atlas of human receptor tyrosine kinases |
| GO:0005515 protein binding | IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 from AI-guided PPI drug discovery study. Reason: MAD1-MAD2 interaction captured in specific annotations. Supporting Evidence: PMID:37398436 AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor |
| GO:0005515 protein binding | IPI PMID:37926298 Therapeutic role of 2-stearoxyphenethyl phosphocholine targe... | MARK AS OVER ANNOTATED | Summary: Interaction with CDC20 from colorectal cancer therapeutic study. Reason: Core CDC20 interaction captured elsewhere. Supporting Evidence: PMID:37926298 Therapeutic role of 2-stearoxyphenethyl phosphocholine targeting microtubule dynamics |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Multiple interactions (BUB1B, CDC27, CDC20, p31comet, EPM2AIP1, MAD1L1) from multimodal cell maps study. Reason: Core interactions captured elsewhere. HTP multimodal study. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics |
| GO:0005515 protein binding | IPI PMID:9092546 Interaction of MAD2 with the carboxyl terminus of the insuli... | MARK AS OVER ANNOTATED | Summary: Interaction with insulin receptor (INSR) documented. MAD2 interacts with insulin receptor C-terminus but not IGF1R. Reason: Interaction with insulin receptor is not clearly related to core checkpoint function. May represent regulatory cross-talk between cell cycle and insulin signaling. Supporting Evidence: PMID:9092546 Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR |
| GO:0042802 identical protein binding | IPI PMID:16525508 Determinants of conformational dimerization of Mad2 and its ... | ACCEPT | Summary: MAD2 homodimerization demonstrated. MAD2 forms conformational heterodimers between O-MAD2 and C-MAD2 forms. Reason: MAD2 homodimerization (O-MAD2:C-MAD2) is essential for the template model of MAD2 activation at kinetochores. This is a core molecular function. Supporting Evidence: PMID:18022367 Third, O-Mad2 and C-Mad2 engage in a "conformational" dimer that is essential for spindle checkpoint function in different organisms PMID:16525508 Determinants of conformational dimerization of Mad2 and its inhibition by p31comet |
| GO:0042802 identical protein binding | IPI PMID:18022367 The Mad2 conformational dimer: structure and implications fo... | ACCEPT | Summary: Crystal structure of O-MAD2:C-MAD2 conformational dimer reported. Essential for checkpoint function. Reason: Landmark structural study establishing the molecular basis of MAD2 conformational dimerization. Core molecular function for SAC signaling. Supporting Evidence: PMID:18022367 The crystal structure of the O-Mad2-C-Mad2 conformational dimer...reveals an asymmetric interface that explains the selective dimerization of the O-Mad2 and C-Mad2 conformers |
| GO:0042802 identical protein binding | IPI PMID:18318601 Insights into mad2 regulation in the spindle checkpoint reve... | ACCEPT | Summary: Crystal structure of symmetric C-MAD2:C-MAD2 dimer reported. Provides insights into MAD2 regulation. Reason: Demonstrates both asymmetric (O-MAD2:C-MAD2) and symmetric (C-MAD2:C-MAD2) dimerization modes. Relevant to understanding MAD2 regulation. Supporting Evidence: PMID:18318601 Insights into mad2 regulation in the spindle checkpoint revealed by the crystal structure of the symmetric mad2 dimer |
| GO:0042802 identical protein binding | IPI PMID:21041666 Phosphorylation of the spindle checkpoint protein Mad2 regul... | ACCEPT | Summary: MAD2 homodimerization studied in context of phosphorylation regulation. Reason: Confirms homodimerization as functionally important and phosphoregulated. Supporting Evidence: PMID:21041666 Phosphorylation of the spindle checkpoint protein Mad2 regulates its conformational transition |
| GO:0042802 identical protein binding | IPI PMID:21772247 Probing the in vivo function of Mad1:C-Mad2 in the spindle a... | ACCEPT | Summary: MAD2 homodimerization confirmed in in vivo functional study. Reason: In vivo validation of MAD2 homodimerization function. Supporting Evidence: PMID:21772247 Probing the in vivo function of Mad1:C-Mad2 in the spindle assembly checkpoint |
| GO:0000775 chromosome, centromeric region | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse ortholog. MAD2 localizes to centromeric regions via kinetochore association. Reason: Kinetochores are located at centromeric regions. This annotation is consistent with MAD2 kinetochore localization. Supporting Evidence: PMID:8824189 Human, or Homo sapiens, MAD2 (hsMAD2) was localized at the kinetochore after chromosome condensation |
| GO:0005694 chromosome | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse ortholog. MAD2 associates with chromosomes via kinetochore localization. Reason: Broader term encompassing kinetochore/centromere localization. Accurate but less specific than kinetochore annotation. Supporting Evidence: PMID:8824189 Human, or Homo sapiens, MAD2 (hsMAD2) was localized at the kinetochore after chromosome condensation |
| GO:0007094 mitotic spindle assembly checkpoint signaling | NAS PMID:11535616 Checkpoint inhibition of the APC/C in HeLa cells is mediated... | ACCEPT | Summary: Non-traceable author statement from study of checkpoint inhibition of APC/C in HeLa cells. MAD2 is part of the MCC that inhibits APC/C. Reason: Core biological process for MAD2. This study describes MCC (BUBR1, BUB3, CDC20, MAD2) mediated APC/C inhibition. Supporting Evidence: PMID:11535616 Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2 |
| GO:0007094 mitotic spindle assembly checkpoint signaling | IMP PMID:23509069 MISP is a novel Plk1 substrate required for proper spindle o... | ACCEPT | Summary: Mutant phenotype evidence from MISP (mitotic spindle positioning) study. MAD2 involvement in spindle checkpoint demonstrated through genetic perturbation. Reason: IMP evidence confirms MAD2 role in SAC signaling. Core biological process. Supporting Evidence: PMID:23509069 MISP is a novel Plk1 substrate required for proper spindle orientation and mitotic progression |
| GO:0090267 positive regulation of mitotic cell cycle spindle assembly checkpoint | IDA PMID:22898774 Evolution and function of the mitotic checkpoint | ACCEPT | Summary: Direct assay evidence from review of mitotic checkpoint evolution and function. MAD2 positively regulates the SAC. Reason: MAD2 activation (O-MAD2 to C-MAD2 conversion) is essential for SAC activation. This is a core regulatory function. Supporting Evidence: PMID:22898774 Evolution and function of the mitotic checkpoint |
| GO:0090267 positive regulation of mitotic cell cycle spindle assembly checkpoint | IDA PMID:8824189 Identification of a human mitotic checkpoint gene: hsMAD2. | ACCEPT | Summary: Original discovery paper demonstrating MAD2 is necessary for mitotic checkpoint function in HeLa cells. Reason: Foundational paper establishing MAD2 as essential for SAC function. Antibody electroporation experiments directly demonstrated MAD2 is required for checkpoint. Supporting Evidence: PMID:8824189 The human homolog of MAD2 was isolated and shown to be a necessary component of the mitotic checkpoint in HeLa cells by antibody electroporation experiments |
| GO:0005515 protein binding | IPI PMID:19010891 Role of a novel splice variant of mitotic arrest deficient 1... | MARK AS OVER ANNOTATED | Summary: Interaction with MAD1L1 isoforms demonstrated. MAD1beta sequesters MAD2 in cytoplasm. Reason: MAD1-MAD2 interaction captured in specific annotations. This study addresses a cancer-associated MAD1 splice variant. Supporting Evidence: PMID:19010891 MAD1beta was found to physically interact with MAD2 and sequester it in the cytoplasm |
| GO:0005634 nucleus | IDA PMID:19010891 Role of a novel splice variant of mitotic arrest deficient 1... | ACCEPT | Summary: Direct assay showing nuclear localization. MAD1alpha is in nucleus while MAD1beta is cytoplasmic, affecting MAD2 localization. Reason: Nuclear localization is validated by multiple studies. MAD2 is recruited to nuclear pore complex by TPR during interphase. Supporting Evidence: PMID:19010891 MAD1alpha was found in the nucleus PMID:18981471 Depletion of Tpr in HeLa cells disrupts the NPC localization of Mad1 and Mad2 during interphase |
| GO:0000776 kinetochore | IDA PMID:8824189 Identification of a human mitotic checkpoint gene: hsMAD2. | ACCEPT | Summary: Original discovery paper showing MAD2 kinetochore localization. MAD2 localizes to kinetochores after chromosome condensation but not at metaphase. Reason: Foundational evidence for MAD2 kinetochore localization. This is core to checkpoint signaling mechanism. Supporting Evidence: PMID:8824189 Human, or Homo sapiens, MAD2 (hsMAD2) was localized at the kinetochore after chromosome condensation but was no longer observed at the kinetochore in metaphase, suggesting that MAD2 might monitor the completeness of the spindle-kinetochore attachment |
| GO:0007094 mitotic spindle assembly checkpoint signaling | IDA PMID:18981471 Tpr directly binds to Mad1 and Mad2 and is important for the... | ACCEPT | Summary: Direct evidence showing TPR binds MAD1 and MAD2 and is important for SAC signaling. MAD2 activation by MAD1 is required for APC-CDC20 inhibition. Reason: Key study establishing TPR role in MAD1-MAD2 regulation. Confirms MAD2 essential role in SAC signaling. Supporting Evidence: PMID:18981471 Depletion of Tpr decreases the levels of Mad1 at kinetochores during prometaphase, correlating with the inability of Mad1 to activate Mad2, which is required for inhibiting APC(Cdc20) |
| GO:0044615 nuclear pore nuclear basket | IDA PMID:18981471 Tpr directly binds to Mad1 and Mad2 and is important for the... | ACCEPT | Summary: Direct evidence showing MAD2 localizes to nuclear pore complex via TPR during interphase. Reason: Important localization for early MCC assembly. TPR is a nuclear pore basket component that recruits MAD1-MAD2 during interphase. Supporting Evidence: PMID:18981471 Depletion of Tpr in HeLa cells disrupts the NPC localization of Mad1 and Mad2 during interphase |
| GO:0005515 protein binding | IPI PMID:25422469 Disruption of FAT10-MAD2 binding inhibits tumor progression | MARK AS OVER ANNOTATED | Summary: Interaction with FAT10/UBD (O15205) demonstrated. Disrupting FAT10-MAD2 binding inhibits tumor progression. Reason: UBD/FAT10 interaction may regulate MAD2 during mitosis but is not part of core checkpoint mechanism. Represents regulatory/peripheral function. Supporting Evidence: PMID:25422469 Disruption of FAT10-MAD2 binding inhibits tumor progression |
| GO:0005515 protein binding | IPI PMID:18794143 HSF1 as a mitotic regulator: phosphorylation of HSF1 by Plk1... | MARK AS OVER ANNOTATED | Summary: Interaction with HSF1 (Q00613) demonstrated. HSF1 interacts with MAD2 during mitosis. Reason: HSF1 interaction occurs during mitosis but is not part of core SAC mechanism. May represent regulatory cross-talk between stress response and cell cycle. Supporting Evidence: PMID:18794143 HSF1 as a mitotic regulator: phosphorylation of HSF1 by Plk1 is essential for mitotic progression |
| GO:0045930 negative regulation of mitotic cell cycle | IMP PMID:21274008 MTBP plays a crucial role in mitotic progression and chromos... | ACCEPT | Summary: Mutant phenotype evidence from study of MTBP role in mitotic progression. MAD2 negatively regulates mitotic cell cycle by preventing premature anaphase. Reason: MAD2-mediated SAC activation delays metaphase-to-anaphase transition, thereby negatively regulating mitotic cell cycle progression. Supporting Evidence: PMID:21274008 MTBP plays a crucial role in mitotic progression and chromosome segregation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-141409 | ACCEPT | Summary: Reactome annotation for MAD1 binding to kinetochore. MAD2 is present in cytosol before activation. Reason: Cytosolic O-MAD2 pool is essential for checkpoint activation. Reactome pathway correctly places MAD2 in cytosol before kinetochore recruitment. Supporting Evidence: PMID:18022367 a catalytic model in which a C-Mad2 template facilitates the binding of O-Mad2 to Cdc20 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-141422 | ACCEPT | Summary: Reactome annotation for MAD2 conversion to inhibitory state via MAD1 interaction. Reason: Cytosolic localization is prerequisite for MAD2 recruitment and activation. Supporting Evidence: PMID:18981471 The mitotic arrest-deficient protein Mad1 forms a complex with Mad2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-141431 | ACCEPT | Summary: Reactome annotation for MAD2 association with MAD1 kinetochore complex. Reason: Consistent with template model of MAD2 activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-141439 | ACCEPT | Summary: Reactome annotation for release of activated MAD2 from kinetochores. Reason: Activated C-MAD2:CDC20 is released to cytosol to form MCC. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1638803 | KEEP AS NON CORE | Summary: Reactome annotation for PLK1 phosphorylation of cohesin at centromeres. Reason: MAD2 involvement in cohesin regulation is secondary to core checkpoint function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1638821 | KEEP AS NON CORE | Summary: Reactome annotation for PP2A-B56 dephosphorylation of centromeric cohesin. Reason: MAD2 involvement in cohesin regulation is secondary to core checkpoint function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2467809 | ACCEPT | Summary: Reactome annotation for ESPL1 (Separase) cleavage of centromeric cohesin. Reason: Cytosolic localization during sister chromatid separation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2467811 | ACCEPT | Summary: Reactome annotation for separation of sister chromatids. Reason: Cytosolic localization during sister chromatid separation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2468287 | KEEP AS NON CORE | Summary: Reactome annotation for CDK1 phosphorylation of CDCA5 (Sororin) at centromeres. Reason: MAD2 involvement in sororin regulation is secondary to core checkpoint function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2484822 | ACCEPT | Summary: Reactome annotation for kinetochore assembly. Reason: Cytosolic MAD2 is recruited during kinetochore assembly. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-375302 | ACCEPT | Summary: Reactome annotation for kinetochore capture of astral microtubules. Reason: Cytosolic localization during spindle assembly. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5666129 | KEEP AS NON CORE | Summary: Reactome annotation for CDC42:GTP recruiting DIAPH2-2 to kinetochores. Reason: MAD2 involvement in DIAPH2 recruitment is secondary to core checkpoint function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5666160 | KEEP AS NON CORE | Summary: Reactome annotation for AURKB phosphorylation of DIAPH2-2 at kinetochores. Reason: MAD2 involvement in DIAPH2 phosphorylation is secondary to core checkpoint function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5666169 | KEEP AS NON CORE | Summary: Reactome annotation for kinetochore capture regulation by CDC42:GTP:p-DIAPH2-2. Reason: MAD2 involvement in this process is secondary to core checkpoint function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9648114 | KEEP AS NON CORE | Summary: Reactome annotation for EML4 recruiting NUDC to mitotic spindle. Reason: MAD2 involvement in EML4-NUDC pathway is secondary to core checkpoint function. |
| GO:0000776 kinetochore | IDA PMID:20133940 Nucleoporin translocated promoter region (Tpr) associates wi... | ACCEPT | Summary: Direct evidence for MAD2 kinetochore localization from TPR-dynein study. Reason: Additional experimental validation of MAD2 kinetochore localization. Supporting Evidence: PMID:20133940 Tpr orchestrates proper chromosome segregation through interaction with dynein light chain...spindle checkpoints Mad1 and Mad2 |
| GO:0005515 protein binding | IPI PMID:20133940 Nucleoporin translocated promoter region (Tpr) associates wi... | MARK AS OVER ANNOTATED | Summary: Interaction with TPR (P12270) demonstrated. Reason: TPR interaction is important for MAD2 NPC localization but "protein binding" is too vague. Functional consequence is captured in localization annotations. Supporting Evidence: PMID:20133940 Here, we show association of another nucleoporin, termed Tpr (translocated promoter region), with the molecular motors dynein and dynactin, which both orchestrate with the spindle checkpoints Mad1 and Mad2 during cell division |
| GO:0072686 mitotic spindle | IDA PMID:20133940 Nucleoporin translocated promoter region (Tpr) associates wi... | ACCEPT | Summary: Direct evidence for MAD2 localization to mitotic spindle. Reason: Mitotic spindle localization is consistent with MAD2 role in SAC signaling. Supporting Evidence: PMID:20133940 Here, we show association of another nucleoporin, termed Tpr (translocated promoter region), with the molecular motors dynein and dynactin |
| GO:0005515 protein binding | IPI PMID:19273613 Spatiotemporal control of mitosis by the conserved spindle m... | MARK AS OVER ANNOTATED | Summary: Interaction with TPR (Megator ortholog) from study of spindle matrix protein. Reason: TPR interaction captured elsewhere. Supporting Evidence: PMID:19273613 Spatiotemporal control of mitosis by the conserved spindle matrix protein Megator |
| GO:0005829 cytosol | TAS Reactome:R-HSA-141423 | ACCEPT | Summary: Reactome annotation for MCC complex binding to APC/C complex. Reason: Core checkpoint mechanism. MCC assembly and APC/C inhibition occur in cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-141429 | ACCEPT | Summary: Reactome annotation for APC/C inactivation via CDC20 sequestration. Reason: Core checkpoint mechanism. CDC20 sequestration by MCC occurs in cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-141437 | ACCEPT | Summary: Reactome annotation for MCC complex formation. Reason: Core checkpoint mechanism. MCC (MAD2, BUBR1, BUB3, CDC20) forms in cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174104 | KEEP AS NON CORE | Summary: Reactome annotation for ubiquitination of Cyclin A by APC/C:Cdc20. Reason: MAD2 in MCC inhibits this reaction. Secondary to core checkpoint signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174171 | KEEP AS NON CORE | Summary: Reactome annotation for Cyclin A association with APC/C. Reason: Secondary pathway annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174238 | ACCEPT | Summary: Reactome annotation for APC/C:Cdc20 activation by MCC dissociation. Reason: Describes checkpoint silencing when MCC dissociates. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174255 | KEEP AS NON CORE | Summary: Reactome annotation for multiubiquitinated Cyclin A degradation. Reason: Downstream consequence of checkpoint silencing. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-179410 | KEEP AS NON CORE | Summary: Reactome annotation for Nek2A association with MCC:APC/C. Reason: MAD2 as part of MCC is involved but this is secondary function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-179417 | KEEP AS NON CORE | Summary: Reactome annotation for Nek2A multiubiquitination. Reason: Secondary pathway annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-179421 | KEEP AS NON CORE | Summary: Reactome annotation for Nek2A degradation. Reason: Secondary pathway annotation. |
| GO:1904667 negative regulation of ubiquitin protein ligase activity | IDA PMID:11459825 Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a... | ACCEPT | Summary: Direct evidence that MAD2-related protein inhibits APC/C ubiquitin ligase activity. Note: This paper primarily studies MAD2L2, not MAD2L1, but proposes mechanism for MAD2 inhibition of APC/C. Reason: MAD2 inhibits APC/C-CDC20 ubiquitin ligase activity through MCC formation. This is a core molecular function of MAD2 in the SAC. Supporting Evidence: PMID:11459825 We suggest that MAD2L2 and MAD2 inhibit the release of substrates from APC and propose a mechanism of inhibition PMID:10700282 The checkpoint protein Mad2 inhibits the activity of the anaphase promoting complex |
| GO:0042177 negative regulation of protein catabolic process | IDA PMID:11459825 Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a... | ACCEPT | Summary: By inhibiting APC/C, MAD2 prevents degradation of APC/C substrates like cyclins and securin. Reason: Accurate annotation. MAD2-mediated MCC inhibition of APC/C prevents ubiquitination and subsequent proteasomal degradation of mitotic substrates. Supporting Evidence: PMID:11459825 We suggest that MAD2L2 and MAD2 inhibit the release of substrates from APC |
| GO:0005634 nucleus | IDA PMID:20870947 Critical role of Pcid2 in B cell survival through the regula... | ACCEPT | Summary: Direct evidence for nuclear localization from Pcid2 study in B cells. Reason: Additional experimental validation of nuclear localization. Supporting Evidence: PMID:20870947 Critical role of Pcid2 in B cell survival through the regulation of MAD2 expression |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:20870947 Critical role of Pcid2 in B cell survival through the regula... | ACCEPT | Summary: Direct evidence for perinuclear localization from Pcid2 study. Reason: Perinuclear localization is consistent with MAD2 association with nuclear pore complex. Supporting Evidence: PMID:20870947 Critical role of Pcid2 in B cell survival through the regulation of MAD2 expression |
| GO:0000776 kinetochore | IDA PMID:19229290 Dynein light intermediate chain 1 is required for progress t... | ACCEPT | Summary: Direct evidence for kinetochore localization from dynein study. Reason: Additional experimental validation of kinetochore localization. Supporting Evidence: PMID:19229290 Dynein light intermediate chain 1 is required for progress through the spindle assembly checkpoint |
| GO:0005515 protein binding | IPI PMID:10200259 A MHC-encoded ubiquitin-like protein (FAT10) binds noncovale... | MARK AS OVER ANNOTATED | Summary: Interaction with FAT10/UBD (O15205) demonstrated. FAT10 binds MAD2 non-covalently. Reason: FAT10 interaction may regulate MAD2 but is not core checkpoint mechanism. Supporting Evidence: PMID:10200259 A MHC-encoded ubiquitin-like protein (FAT10) binds noncovalently to the spindle assembly checkpoint protein MAD2 |
| GO:0005515 protein binding | IPI PMID:15525512 Phosphorylation of Cdc20 by Bub1 provides a catalytic mechan... | MARK AS OVER ANNOTATED | Summary: Interaction with CDC20 documented. Study of BUB1 phosphorylation of CDC20. Reason: Core CDC20 interaction captured in more specific annotations. Supporting Evidence: PMID:15525512 Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint |
| GO:0005515 protein binding | IPI PMID:10700282 Structure of the Mad2 spindle assembly checkpoint protein an... | MODIFY | Summary: Seminal structural study showing MAD2-CDC20 interaction. MAD2 C-terminal region binds CDC20. Reason: This is the primary MAD2-CDC20 interaction paper. Should be annotated to more specific complex term. Proposed replacements: mitotic checkpoint complex, CDC20-MAD2 subcomplex Supporting Evidence: PMID:10700282 Mad2 and Cdc20 form a tight 1:1 heterodimeric complex in which the C-terminal segment of Mad2 becomes folded |
| GO:0000776 kinetochore | IDA PMID:19468067 Mitotic control of kinetochore-associated dynein and spindle... | ACCEPT | Summary: Colocalization with kinetochore markers from Spindly study. Reason: Additional experimental validation of kinetochore localization. Supporting Evidence: PMID:19468067 Mitotic control of kinetochore-associated dynein and spindle orientation by human Spindly |
| GO:0000776 kinetochore | IDA PMID:17363900 The human Nup107-160 nuclear pore subcomplex contributes to ... | ACCEPT | Summary: Colocalization evidence from Nup107-160 nuclear pore subcomplex study. Reason: Additional experimental validation of kinetochore localization. Supporting Evidence: PMID:17363900 The human Nup107-160 nuclear pore subcomplex contributes to proper kinetochore functions |
| GO:0005515 protein binding | IPI PMID:18981471 Tpr directly binds to Mad1 and Mad2 and is important for the... | MODIFY | Summary: Interaction with TPR (P12270) demonstrated. TPR directly binds MAD1 and MAD2. Reason: TPR interaction is functionally important for MAD2 NPC localization during interphase. Should be captured with more specific term if available. Proposed replacements: nuclear pore nuclear basket Supporting Evidence: PMID:18981471 Tpr directly binds to Mad1 and Mad2 |
| GO:0005634 nucleus | IDA PMID:18981471 Tpr directly binds to Mad1 and Mad2 and is important for the... | ACCEPT | Summary: Direct evidence for nuclear localization via TPR association. Reason: Key study establishing MAD2 NPC localization during interphase. Supporting Evidence: PMID:18981471 Depletion of Tpr in HeLa cells disrupts the NPC localization of Mad1 and Mad2 during interphase |
| GO:0005829 cytosol | IDA PMID:18981471 Tpr directly binds to Mad1 and Mad2 and is important for the... | ACCEPT | Summary: Direct evidence for cytosolic localization. O-MAD2 pool is cytosolic. Reason: Cytosolic localization is essential for template model of MAD2 activation. Supporting Evidence: PMID:18981471 Tpr directly binds to Mad1 and Mad2...decreases the levels of Mad1-bound Mad2 |
| GO:0042803 protein homodimerization activity | IPI PMID:18022367 The Mad2 conformational dimer: structure and implications fo... | ACCEPT | Summary: Seminal structural study demonstrating MAD2 homodimerization. O-MAD2:C-MAD2 conformational dimer is essential for checkpoint function. Reason: This is a core molecular function of MAD2. The conformational dimer enables template-based activation of O-MAD2 to C-MAD2. Supporting Evidence: PMID:18022367 Third, O-Mad2 and C-Mad2 engage in a "conformational" dimer that is essential for spindle checkpoint function in different organisms |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:8824189 Identification of a human mitotic checkpoint gene: hsMAD2. | ACCEPT | Summary: Original discovery paper noting MAD2 perinuclear localization. Reason: Perinuclear localization consistent with NPC association. Supporting Evidence: PMID:8824189 Identification of a human mitotic checkpoint gene: hsMAD2 |
| GO:0005515 protein binding | IPI PMID:12006501 Crystal structure of the tetrameric Mad1-Mad2 core complex: ... | MODIFY | Summary: Interaction with MAD1L1 demonstrated in structural study of tetrameric Mad1-Mad2 core complex. Reason: This is a core functional interaction. The MAD1-MAD2 complex is essential for checkpoint signaling. Should be annotated to specific complex term. Proposed replacements: mitotic spindle assembly checkpoint MAD1-MAD2 complex Supporting Evidence: PMID:12006501 The crystal structure of the Mad1-Mad2 complex reveals an asymmetric tetramer, with elongated Mad1 monomers parting from a coiled-coil to form two connected sub-complexes with Mad2 |
| GO:0033597 mitotic checkpoint complex | IDA PMID:11535616 Checkpoint inhibition of the APC/C in HeLa cells is mediated... | NEW | Summary: MAD2 is a core component of the mitotic checkpoint complex (MCC) which consists of MAD2, BUBR1/MAD3, BUB3, and CDC20 in mammals. Reason: The MCC annotation should be added as it represents a core complex for MAD2 function in SAC signaling. The MCC inhibits APC/C-CDC20 to prevent premature anaphase. Supporting Evidence: PMID:11535616 Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2 PMID:10700282 The checkpoint protein Mad2 inhibits the activity of the anaphase promoting complex by sequestering Cdc20 |
| GO:1990948 ubiquitin ligase inhibitor activity | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:10700282 The checkpoint protein Mad2 inhibits the activity of the anaphase promoting complex by sequestering Cdc20 PMID:11459825 We suggest that MAD2L2 and MAD2 inhibit the release of substrates from APC |
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Download this section (compressed HTML)Q: How does MAD2 conformational switching (O-MAD2 to C-MAD2) contribute to the amplification of checkpoint signaling?
Q: What are the structural determinants of the asymmetric O-MAD2:C-MAD2 dimer interface?
Q: How do post-translational modifications regulate MAD2 activity and localization?
Experiment: Live-cell imaging with MAD2 conformer-specific probes to track O-MAD2 to C-MAD2 conversion in real time
Hypothesis: Real-time tracking of MAD2 conformational changes will reveal the kinetics of checkpoint activation
Experiment: Reconstitution of MCC assembly on phosphorylated kinetochore scaffolds
Hypothesis: Phosphorylation state of kinetochore components regulates the efficiency of MCC assembly
Experiment: Structural analysis of MAD2 variants associated with checkpoint defects in cancer
Hypothesis: Cancer-associated MAD2 mutations disrupt key interfaces required for dimerization or ligand binding
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