Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007254 JNK cascade	IBA GO_REF:0000033	ACCEPT	Summary: ASK1 is a well-established upstream activator of the JNK cascade. The original discovery paper (Ichijo et al., 1997, PMID:8974401) demonstrated that ASK1 "activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK)." Multiple subsequent studies confirm ASK1 involvement in JNK cascade activation via MKK4/MKK7 phosphorylation. The IBA annotation is phylogenetically supported and represents a core function. Reason: JNK cascade involvement is the core function of ASK1. The IBA annotation is well-supported by extensive literature showing ASK1 directly phosphorylates MKK4/MKK7 to activate JNK. Supporting Evidence: PMID:8974401 A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6) file:human/MAP3K5/MAP3K5-deep-research-falcon.md See deep research file for comprehensive analysis
GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress	IBA GO_REF:0000033	ACCEPT	Summary: ASK1 is a key mediator of oxidative stress-induced apoptosis. Under basal conditions, thioredoxin (TXN) binds to and inhibits ASK1. Oxidative stress causes oxidation of thioredoxin, leading to its dissociation from ASK1 and subsequent ASK1 activation. This mechanism is well-documented (PMID:9564042, PMID:10688666). The UniProt record confirms "Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation." Reason: Oxidative stress-induced apoptotic signaling is a well-established core function of ASK1, mediated through thioredoxin dissociation and JNK/p38 activation. Supporting Evidence: PMID:21771788 ZPR9 functionally stimulated ASK1-induced AP-1 transcriptional activity as well as H(2)O(2)-mediated apoptosis PMID:26095851 ASK1 is known to induce caspase-3 activation and apoptosis
GO:0038066 p38MAPK cascade	IBA GO_REF:0000033	ACCEPT	Summary: ASK1 directly phosphorylates MKK3/MKK6 to activate the p38 MAPK cascade. The original discovery paper (Ichijo et al., 1997, PMID:8974401) identified ASK1 as activating "MKK3/MAPKK6 (or MKK6), which in turn activated...p38 subgroups of MAP kinases." UniProt confirms ASK1 "acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7." Reason: p38MAPK cascade activation is a core function of ASK1, parallel to JNK cascade activation, both representing the primary downstream outputs of this MAP3K. Supporting Evidence: PMID:8974401 A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively
GO:0051402 neuron apoptotic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: ASK1 has been implicated in neuronal apoptosis, particularly in context of polyglutamine diseases and neurodegeneration. PMID:12050113 demonstrated "ASK1(-/-) primary neurons are defective in polyQ-, proteasome inhibitor-, and ER stress-induced JNK activation and cell death." PMID:15983381 showed DJ-1 protects neurons by sequestering Daxx and preventing ASK1 activation. While relevant to neuronal contexts, this is a downstream consequence of ASK1 activation rather than a core molecular function. Reason: Neuronal apoptosis is a context-dependent outcome of ASK1 activation, particularly relevant in neurodegenerative disease. While well-documented, it represents a downstream phenotypic consequence rather than the core enzymatic function. Supporting Evidence: PMID:12050113 ASK1(-/-) primary neurons are defective in polyQ-, proteasome inhibitor-, and ER stress-induced JNK activation and cell death PMID:15983381 wild-type DJ-1 sequesters Daxx in the nucleus, prevents it from gaining access to the cytoplasm, from binding to and activating its effector kinase apoptosis signal-regulating kinase 1
GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IBA GO_REF:0000033	ACCEPT	Summary: ASK1 is essential for ER stress-induced apoptosis. PMID:12050113 demonstrated that "ER stress activates ASK1 through formation of an IRE1-TRAF2-ASK1 complex" and "ASK1(-/-) primary neurons are defective in...ER stress-induced JNK activation and cell death." PMID:23000344 confirmed "ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling." This represents a core stress-response function. Reason: ER stress-induced apoptotic signaling via the IRE1-TRAF2-ASK1 complex is a well-established core function of ASK1, essential for ER stress responses. Supporting Evidence: PMID:12050113 ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex PMID:23000344 Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling
GO:0004709 MAP kinase kinase kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: MAP kinase kinase kinase activity is the defining molecular function of ASK1. The original discovery (PMID:8974401) identified ASK1 as "a MAP kinase kinase kinase (MAPKKK)...that activated two different subgroups of MAP kinase kinases (MAPKK)." UniProt assigns EC 2.7.11.25 with evidence from PMID:26095851. The structural study (PMID:17937911) confirmed the kinase domain structure and activity. Reason: MAP kinase kinase kinase activity is the core molecular function of ASK1. This is the primary enzymatic activity of the protein. Supporting Evidence: PMID:8974401 A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK) PMID:17937911 ASK1 activates both the JNK and p38 pathways by direct phosphorylation of MAP kinase kinases (MKKs)
GO:0000165 MAPK cascade	IEA GO_REF:0000002	ACCEPT	Summary: MAPK cascade involvement is correct but very general. ASK1 specifically activates the stress-activated MAPK cascades (JNK and p38), not the classical ERK pathway. The more specific annotations for JNK cascade (GO:0007254) and p38MAPK cascade (GO:0038066) are preferred. Reason: While correct and acceptable as a broader parent term, the more specific JNK cascade and p38MAPK cascade annotations capture the actual function better. This IEA annotation provides appropriate general coverage.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: ASK1 binds ATP as part of its kinase activity. However, this term is very general. The more specific term ATP binding (GO:0005524) is more informative for a kinase. Reason: Nucleotide binding is technically correct but too general for a kinase. ATP binding (GO:0005524) is more specific and informative.
GO:0002376 immune system process	IEA GO_REF:0000043	MODIFY	Summary: ASK1 plays a role in innate immune responses. UniProt notes "MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens." However, this term is very broad. Reason: While ASK1 is involved in immune processes, this term is too general. The more specific term "innate immune response" (GO:0045087) better captures the role. Proposed replacements: innate immune response
GO:0004672 protein kinase activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Protein kinase activity is correct but redundant with the more specific MAP kinase kinase kinase activity (GO:0004709). ASK1 is specifically a MAP3K, not a general protein kinase. Reason: Protein kinase activity is technically correct but redundant with the more specific MAP kinase kinase kinase activity. The more specific term should be preferred.
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: ASK1 is indeed a serine/threonine kinase, but this term is redundant with MAP kinase kinase kinase activity (GO:0004709) which is more specific. MAP3Ks are by definition serine/threonine kinases. Reason: Redundant with the more specific MAP kinase kinase kinase activity term. MAP3Ks are serine/threonine kinases by definition.
GO:0004709 MAP kinase kinase kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: This is a duplicate annotation for MAP kinase kinase kinase activity from a different IEA source. The annotation is correct and represents the core function. Reason: Duplicate of the IBA annotation for the same term. Both are correct and acceptable - duplicates are fine in GO annotations when from different sources.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: ATP binding is essential for kinase function. PMID:17210579 demonstrated ASK1 ATP binding experimentally, and the crystal structure (PMID:17937911) shows staurosporine bound in the ATP binding site. Reason: ATP binding is required for kinase activity and is experimentally validated by structural and biochemical studies. Supporting Evidence: PMID:17937911 The hinge region connecting the two domains lines the catalytic ATP binding site, which is occupied by the ATP competitive inhibitor staurosporine
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: ASK1 is primarily cytoplasmic. UniProt states "Cytoplasm" as subcellular location. Multiple studies confirm cytoplasmic localization. PMID:26095851 demonstrates cytoplasmic localization. The more specific term cytosol (GO:0005829) may be more accurate. Reason: Cytoplasmic localization is correct and well-documented. This broader term is acceptable alongside the more specific cytosol annotations.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000044	ACCEPT	Summary: ASK1 localizes to the ER in the context of the IRE1-TRAF2-ASK1 complex during ER stress. UniProt notes "Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region." This is a conditional localization during ER stress responses. Reason: ER localization is correct in the context of ER stress signaling via the IRE1-TRAF2-ASK1 complex. This represents functional localization during stress responses. Supporting Evidence: PMID:12050113 ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex
GO:0006915 apoptotic process	IEA GO_REF:0000043	ACCEPT	Summary: ASK1 is intimately involved in apoptosis. The original paper (PMID:8974401) demonstrated "Overexpression of ASK1 induced apoptotic cell death." However, more specific apoptotic signaling pathway terms better capture the role. Reason: Apoptotic process involvement is a well-established function of ASK1, though more specific terms like apoptotic signaling pathway better describe the mechanism. Supporting Evidence: PMID:8974401 Overexpression of ASK1 induced apoptotic cell death
GO:0016301 kinase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Kinase activity is correct but very general. More specific terms (MAP kinase kinase kinase activity, protein kinase activity) are more informative. Reason: Too general; more specific kinase activity terms exist for ASK1.
GO:0016740 transferase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Transferase activity is technically correct (kinases are phosphotransferases) but extremely general and uninformative for annotation purposes. Reason: Too general; more specific terms are available that better describe ASK1 function.
GO:0045087 innate immune response	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: ASK1 plays a role in innate immunity. UniProt states "MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens." ASK1 knockout mice are resistant to LPS-induced septic shock. This is a legitimate biological process annotation. Reason: Innate immune response is a documented function of ASK1 but represents a downstream consequence of its stress-responsive kinase activity rather than its core molecular function.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MODIFY	Summary: Kinases typically bind divalent metal ions (Mg2+) as cofactors. UniProt lists Mg2+ as a cofactor. However, this general term is less informative than the specific magnesium ion binding annotation. Reason: Metal ion binding is correct but too general. Magnesium ion binding (GO:0000287) is more specific and appropriate. Proposed replacements: magnesium ion binding
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	MARK AS OVER ANNOTATED	Summary: ASK1 has protein serine kinase activity. UniProt lists the catalytic activity as phosphorylating L-seryl-[protein] with EC 2.7.11.25. However, the more specific MAP kinase kinase kinase activity term is preferred. Reason: Correct but redundant with MAP kinase kinase kinase activity. MAP3Ks phosphorylate serine/threonine residues by definition.
GO:0005515 protein binding	IPI PMID:11003656 Inhibition of Daxx-mediated apoptosis by heat shock protein ...	MARK AS OVER ANNOTATED	Summary: This protein binding annotation refers to interaction with Daxx (Q9UER7). ASK1-Daxx interaction is functionally important for apoptosis signaling. However, "protein binding" is uninformative - more specific terms would be preferred. Reason: Protein binding is too general and uninformative. The ASK1-Daxx interaction has functional significance but generic protein binding does not capture the biological meaning. Supporting Evidence: PMID:11003656 Inhibition of Daxx-mediated apoptosis by heat shock protein 27.
GO:0005515 protein binding	IPI PMID:11154276 Akt phosphorylates and negatively regulates apoptosis signal...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with AKT1 (P31749). AKT1 phosphorylates ASK1 at Ser83 to inhibit its activity. This is a regulatory interaction but "protein binding" is uninformative. Reason: Protein binding is too general. The AKT1-ASK1 interaction represents regulatory phosphorylation, not just binding. Supporting Evidence: PMID:11154276 Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1
GO:0005515 protein binding	IPI PMID:11298454 HIV-1 Nef inhibits ASK1-dependent death signalling providing...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with HIV-1 Nef. UniProt notes "HIV-1 Nef inhibits MAP3K5/ASK1 signaling." This represents viral evasion mechanism, and protein binding is uninformative. Reason: Protein binding is too general for annotation purposes, even though the interaction is biologically significant. Supporting Evidence: PMID:11298454 HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell.
GO:0005515 protein binding	IPI PMID:11495919 Apoptosis signal-regulating kinase 1 controls the proapoptot...	MARK AS OVER ANNOTATED	Summary: This annotation refers to Daxx interaction (Q9UER7), duplicate of PMID:11003656. Protein binding remains uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:11495919 2001 Aug 8. Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm.
GO:0005515 protein binding	IPI PMID:12813029 AIP1 mediates TNF-alpha-induced ASK1 activation by facilitat...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with DAB2IP/AIP1 (Q5VWQ8). AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. Functionally important but protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:12813029 AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3.
GO:0005515 protein binding	IPI PMID:14557248 Identification of a novel antiapoptotic protein that antagon...	MARK AS OVER ANNOTATED	Summary: Protein binding annotation from IntAct. Generic and uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:14557248 Identification of a novel antiapoptotic protein that antagonizes ASK1 and CAD activities.
GO:0005515 protein binding	IPI PMID:15023544 Interaction of apoptosis signal-regulating kinase 1 with iso...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with 14-3-3 proteins (YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ, SFN). 14-3-3 binding at phospho-Ser966 inhibits ASK1 activity. This is a critical regulatory interaction but protein binding is uninformative. Reason: Protein binding is too general. The 14-3-3 interaction is functionally critical for ASK1 regulation. Supporting Evidence: PMID:15023544 Interaction of apoptosis signal-regulating kinase 1 with isoforms of 14-3-3 proteins.
GO:0005515 protein binding	IPI PMID:16449798 Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MA...	MARK AS OVER ANNOTATED	Summary: Protein binding annotation referencing 14-3-3 zeta. Uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:16449798 Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice.
GO:0005515 protein binding	IPI PMID:16636664 Human glutathione S-transferase P1-1 interacts with TRAF2 an...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with GSTP1 (Q12933). GSTP1 regulates TRAF2-ASK1 signals. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:16636664 Apr 24. Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals.
GO:0005515 protein binding	IPI PMID:16648474 Direct interaction and reciprocal regulation between ASK1 an...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with calcineurin regulatory subunit PPP3R1 (P63098). Calcineurin dephosphorylates ASK1 Ser966. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:16648474 Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth.
GO:0005515 protein binding	IPI PMID:17210579 Apoptosis signal-regulating kinase (ASK) 2 functions as a mi...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with ASK2/MAP3K6 (Q9WTR2 - mouse). ASK1 forms heteromeric complexes with ASK2 that are important for stress signaling. Protein binding is uninformative but the interaction is functionally important. Reason: Protein binding is too general. ASK1-ASK2 heteromerization is functionally important but not captured by generic protein binding. Supporting Evidence: PMID:17210579 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
GO:0005515 protein binding	IPI PMID:17700517 G1 to S phase transition protein 1 induces apoptosis signal-...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with 14-3-3 eta (Q04917). Generic protein binding annotation. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:17700517 Aug 20. G1 to S phase transition protein 1 induces apoptosis signal-regulating kinase 1 activation by dissociating 14-3-3 from ASK1.
GO:0005515 protein binding	IPI PMID:19590015 Mitochondrial phosphoglycerate mutase 5 uses alternate catal...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with PGAM5 (Q96HS1). PGAM5 dephosphorylates and activates ASK1. Important regulatory interaction but protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:19590015 Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1.
GO:0005515 protein binding	IPI PMID:19782076 A scanning peptide array approach uncovers association sites...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with beta-arrestin 2 (ARRB2, P32121). ARRB2 serves as a scaffold for JNK3 activation. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:19782076 Epub 2009 Sep 24. A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex.
GO:0005515 protein binding	IPI PMID:19805025 CIB1 functions as a Ca(2+)-sensitive modulator of stress-ind...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with thioredoxin (TXN, P10599) and other proteins. TXN-ASK1 interaction is critical for ASK1 regulation. However, protein binding is uninformative. Reason: Protein binding is too general. The TXN-ASK1 interaction is the key regulatory mechanism for ASK1 but is not captured by generic protein binding. Supporting Evidence: PMID:19805025 CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1.
GO:0005515 protein binding	IPI PMID:19935702 Dual engagement of 14-3-3 proteins controls signal relay fro...	MARK AS OVER ANNOTATED	Summary: Protein binding annotation from IntAct. Generic and uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:19935702 Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome.
GO:0005515 protein binding	IPI PMID:21496457 Stabilization of the survival motor neuron protein by ASK1.	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with SMN (Q16637). Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:21496457 2011 Apr 9. Stabilization of the survival motor neuron protein by ASK1.
GO:0005515 protein binding	IPI PMID:21771788 Positive regulation of apoptosis signal-regulating kinase 1 ...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interactions with TXN, 14-3-3, MAP2K3, and ZPR9 demonstrated in PMID:21771788. These are functionally important interactions but protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:21771788 2011 Jul 19. Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein.
GO:0005515 protein binding	IPI PMID:22609355 Microspherule protein 2 associates with ASK1 and acts as a n...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with MCRS1 (Q96EZ8). Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:22609355 Epub 2012 May 15. Microspherule protein 2 associates with ASK1 and acts as a negative regulator of stress-induced ASK1 activation.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: This annotation from proximity ligation assay data. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:25241761 Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
GO:0005515 protein binding	IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo...	MARK AS OVER ANNOTATED	Summary: Protein binding annotation from kinase network analysis. Uninformative. Reason: Protein binding is too general and uninformative. 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:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome study. Protein binding is uninformative. Reason: Protein binding is too general and uninformative for functional annotation. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome study. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: High-throughput neurodegenerative disease interactome study. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: High-throughput proteome-scale interactome study. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: OpenCell endogenous tagging study. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding	IPI PMID:9743501 Activation of apoptosis signal-regulating kinase 1 (ASK1) by...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with Daxx (Q9UER7). PMID:9743501 demonstrated "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx." Functionally important but protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:9743501 Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx.
GO:0042802 identical protein binding	IPI PMID:17937911 Structural and functional characterization of the human prot...	ACCEPT	Summary: ASK1 homodimerization is well-documented. PMID:17937911 demonstrated by analytical ultracentrifugation that "the ASK1 catalytic domain is dimeric in solution" with "determination of a dissociation constant (KD) of 0.22 +/- 0.2 microM." PMID:11920685 showed "ASK1 appears to form a silent homo-oligomer through its C-terminal coiled-coil region." This is more informative than generic protein binding. Reason: Identical protein binding (homodimerization) is a well-documented and functionally important property of ASK1. Homodimerization is required for activation. Supporting Evidence: PMID:17937911 Sedimentation velocity measurements led to the determination of...a protein molecular weight of 66 kDa, which is in excellent agreement with the expected mass of an ASK1 catalytic domain dimer PMID:11920685 ASK1 appears to form a silent homo-oligomer through its C-terminal coiled-coil region in non-stressed cells
GO:0042802 identical protein binding	IPI PMID:19805025 CIB1 functions as a Ca(2+)-sensitive modulator of stress-ind...	ACCEPT	Summary: Additional evidence for ASK1 homodimerization. Acceptable duplicate annotation from different source. Reason: Homodimerization is a well-documented property of ASK1. Supporting Evidence: PMID:19805025 CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1.
GO:0042802 identical protein binding	IPI PMID:9743501 Activation of apoptosis signal-regulating kinase 1 (ASK1) by...	ACCEPT	Summary: Additional evidence for ASK1 homodimerization from early study. Acceptable duplicate annotation from different source. Reason: Homodimerization is a well-documented property of ASK1. Supporting Evidence: PMID:9743501 Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx.
GO:0019901 protein kinase binding	IEA GO_REF:0000107	ACCEPT	Summary: ASK1 binds multiple protein kinases including AKT1, PIM1, and downstream MAP2Ks. This is more informative than generic protein binding but still fairly general for a kinase that both phosphorylates and is phosphorylated by other kinases. Reason: Protein kinase binding is a legitimate function given ASK1 interactions with MAP2Ks and upstream kinases.
GO:0034976 response to endoplasmic reticulum stress	IEA GO_REF:0000107	ACCEPT	Summary: ASK1 is essential for ER stress responses via the IRE1-TRAF2-ASK1 complex. PMID:12050113 demonstrated "ER stress activates ASK1" and PMID:23000344 showed ER stress induces IRE1-TRAF2-ASK1 complex formation. This is a core function. Reason: Response to ER stress is a well-documented core function of ASK1. Supporting Evidence: PMID:12050113 ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex
GO:0038066 p38MAPK cascade	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate annotation for p38MAPK cascade from different evidence source. Core function of ASK1. Reason: p38MAPK cascade is a core function, duplicate from different source is acceptable.
GO:0043065 positive regulation of apoptotic process	IEA GO_REF:0000107	ACCEPT	Summary: ASK1 overexpression induces apoptosis (PMID:8974401). PMID:21771788 showed "ZPR9 functionally stimulated ASK1-induced AP-1 transcriptional activity as well as H(2)O(2)-mediated apoptosis." Pro-apoptotic function is well-established. Reason: Positive regulation of apoptosis is a well-documented function of ASK1, representing a core downstream outcome of its kinase activity. Supporting Evidence: PMID:8974401 Overexpression of ASK1 induced apoptotic cell death
GO:0045663 positive regulation of myoblast differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: ASK1 has been implicated in cellular differentiation in some contexts. UniProt notes ASK1 "may also promote differentiation and survival" depending on context. This is not a core function but represents context-dependent effects. Reason: Myoblast differentiation is a context-dependent effect of ASK1 signaling, not a core function.
GO:0046330 positive regulation of JNK cascade	IEA GO_REF:0000107	ACCEPT	Summary: ASK1 positively regulates JNK cascade by phosphorylating MKK4/MKK7. This is a core function. Reason: Positive regulation of JNK cascade is a core function of ASK1.
GO:0051402 neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Duplicate annotation for neuron apoptotic process from different source. Context-dependent function. Reason: Neuron apoptosis is context-dependent, not core function.
GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate annotation for ER stress-induced apoptosis from different source. Core function. Reason: ER stress-induced apoptotic signaling is a core function.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosolic localization confirmed by immunofluorescence (HPA). UniProt lists cytoplasm as subcellular location. PMID:26095851 confirms cytoplasmic localization. Reason: Cytosolic localization is well-documented for ASK1. Supporting Evidence: PMID:26095851 Cyclophilin A (CypA), a member of the immunophilin family, is predominantly localized in the cytoplasm
GO:0090398 cellular senescence	TAS Reactome:R-HSA-2559583	KEEP AS NON CORE	Summary: ASK1 is involved in cellular senescence via the oxidative stress induced senescence pathway. Recent research (2024) confirms ASK1 drives SASP via p38 during senescence. This is a legitimate biological process. Reason: Cellular senescence is a downstream consequence of ASK1-mediated stress signaling, not a core function.
GO:0004674 protein serine/threonine kinase activity	TAS Reactome:R-HSA-3228469	MARK AS OVER ANNOTATED	Summary: Reactome pathway "MAP3K5 phosphorylates MKK3 and MKK6." This TAS annotation confirms kinase activity. Redundant with MAP3K activity. Reason: Redundant with more specific MAP kinase kinase kinase activity term.
GO:0004674 protein serine/threonine kinase activity	TAS Reactome:R-NUL-3299417	MARK AS OVER ANNOTATED	Summary: Reactome pathway "MAP3K5 (ASK1) phosphorylates Map2k4(Sek1)." Duplicate TAS annotation for kinase activity. Redundant with MAP3K activity. Reason: Redundant with more specific MAP kinase kinase kinase activity term.
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:15983381 Interaction of DJ-1 with Daxx inhibits apoptosis signal-regu...	ACCEPT	Summary: PMID:15983381 demonstrated ASK1 kinase activity. The paper states DJ-1 "prevents it from gaining access to the cytoplasm, from binding to and activating its effector kinase apoptosis signal-regulating kinase 1." This confirms ASK1 kinase activity. Reason: MAP3K activity is the core molecular function, experimentally validated. Supporting Evidence: PMID:15983381 We demonstrate that wild-type DJ-1 sequesters Daxx in the nucleus, prevents it from gaining access to the cytoplasm, from binding to and activating its effector kinase apoptosis signal-regulating kinase 1
GO:0046330 positive regulation of JNK cascade	IMP PMID:23000344 Ursolic acid induces ER stress response to activate ASK1-JNK...	ACCEPT	Summary: PMID:23000344 demonstrated "ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling." IMP evidence for JNK cascade activation. Reason: Core function with experimental evidence. Supporting Evidence: PMID:23000344 Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling
GO:0019903 protein phosphatase binding	IPI PMID:20674765 Protein phosphatase with EF-hand domains 2 (PPEF2) is a pote...	ACCEPT	Summary: PMID:20674765 demonstrated ASK1 interaction with PPEF2 phosphatase. "We identify human PPEF2 as a novel interacting partner and a negative regulator of ASK1." ASK1 also binds PP5/PPP5C. Phosphatase binding is relevant for ASK1 regulation. Reason: Protein phosphatase binding is a legitimate molecular function annotation given ASK1 regulation by multiple phosphatases. Supporting Evidence: PMID:20674765 We identify human PPEF2 as a novel interacting partner and a negative regulator of ASK1
GO:0097190 apoptotic signaling pathway	IDA PMID:20674765 Protein phosphatase with EF-hand domains 2 (PPEF2) is a pote...	ACCEPT	Summary: PMID:20674765 demonstrated "expression of PPEF2 abrogated sustained activation of p38 and one of the JNK p46 isoforms, and prevented ASK1-dependent caspase-3 cleavage and activation." This confirms ASK1 involvement in apoptotic signaling. Reason: Apoptotic signaling pathway is a well-documented function of ASK1. Supporting Evidence: PMID:20674765 In COS-7 or HEK 293A cells treated with H(2)O(2), expression of PPEF2 abrogated sustained activation of p38 and one of the JNK p46 isoforms, and prevented ASK1-dependent caspase-3 cleavage and activation
GO:0051402 neuron apoptotic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation based on mouse ortholog. Mouse ASK1 knockout neurons are resistant to stress-induced apoptosis (PMID:12050113). Context-dependent. Reason: Neuron apoptosis is context-dependent, not core function.
GO:0036480 neuron intrinsic apoptotic signaling pathway in response to oxidative stress	IGI PMID:15983381 Interaction of DJ-1 with Daxx inhibits apoptosis signal-regu...	KEEP AS NON CORE	Summary: PMID:15983381 studied DJ-1 interaction with Daxx and ASK1 in context of Parkinson disease. Shows ASK1 involved in neuronal oxidative stress-induced apoptosis. Very specific and context-dependent. Reason: This is a highly specific context-dependent annotation for neuronal apoptosis, not a core general function. Supporting Evidence: PMID:15983381 Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death.
GO:0005515 protein binding	IPI PMID:22095282 Arginine methylation-dependent regulation of ASK1 signaling ...	MARK AS OVER ANNOTATED	Summary: PMID:22095282 demonstrated ASK1 interaction with TRAF2 and PRMT1. PRMT1 methylates ASK1 to inhibit its activation. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:22095282 Nov 18. Arginine methylation-dependent regulation of ASK1 signaling by PRMT1.
GO:0007254 JNK cascade	IMP PMID:22095282 Arginine methylation-dependent regulation of ASK1 signaling ...	ACCEPT	Summary: PMID:22095282 demonstrated that PRMT1 "negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 activation" of JNK. IMP evidence for JNK cascade involvement. Reason: JNK cascade is a core function, supported by experimental evidence. Supporting Evidence: PMID:22095282 Nov 18. Arginine methylation-dependent regulation of ASK1 signaling by PRMT1.
GO:0004706 JUN kinase kinase kinase activity	IDA PMID:11959862 Scaffold role of a mitogen-activated protein kinase phosphat...	ACCEPT	Summary: PMID:11959862 demonstrated ASK1 activates MKK7 which activates JNK. "SKRP1 selectively formed the stable complexes with MKK7...SKRP1 also interacted with the MAPKKK, apoptosis signal-regulating kinase 1 (ASK1)... SKRP1 expression...specifically enhanced the activation of MKK7 by ASK1." JNK kinase kinase kinase activity is more specific than general MAP3K activity. Reason: JUN kinase kinase kinase activity is a more specific term capturing ASK1 activation of the JNK pathway via MKK4/MKK7. Supporting Evidence: PMID:11959862 SKRP1 expression increased the ASK1-MKK7 complexes in a dose-dependent manner and specifically enhanced the activation of MKK7 by ASK1
GO:0007254 JNK cascade	IDA PMID:11959862 Scaffold role of a mitogen-activated protein kinase phosphat...	ACCEPT	Summary: PMID:11959862 provides IDA evidence for ASK1 in JNK cascade via ASK1-MKK7 interaction. Core function. Reason: JNK cascade is a core function with direct experimental evidence. Supporting Evidence: PMID:11959862 2002 Apr 16. Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway.
GO:0005515 protein binding	IPI PMID:26095851 Cyclophilin A regulates JNK/p38-MAPK signaling through its p...	MARK AS OVER ANNOTATED	Summary: PMID:26095851 demonstrated ASK1 interaction with cyclophilin A (PPIA). "CypA negatively regulates phosphorylation of ASK1 at Ser966." Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:26095851 Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1.
GO:0005737 cytoplasm	IDA PMID:26095851 Cyclophilin A regulates JNK/p38-MAPK signaling through its p...	ACCEPT	Summary: PMID:26095851 shows ASK1 cytoplasmic localization. Acceptable localization annotation. Reason: Cytoplasmic localization is well-documented. Supporting Evidence: PMID:26095851 Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1.
GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress	IDA PMID:26095851 Cyclophilin A regulates JNK/p38-MAPK signaling through its p...	ACCEPT	Summary: PMID:26095851 demonstrates ASK1 involvement in oxidative stress-induced apoptosis. "ASK1 is known to induce caspase-3 activation and apoptosis, and CypA inhibited ASK1-mediated apoptosis by decrease in caspase-3 activity under cellular stress conditions." Reason: Core function with experimental evidence. Supporting Evidence: PMID:26095851 ASK1 is known to induce caspase-3 activation and apoptosis
GO:0005515 protein binding	IPI PMID:15246877 S-nitrosation of thioredoxin in the nitrogen monoxide/supero...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with thioredoxin (P10599). TXN-ASK1 interaction is critical for regulation but protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:15246877 S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system activates apoptosis signal-regulating kinase 1.
GO:0005515 protein binding	IPI PMID:17761141 Connexin 43 confers resistance to hydrogen peroxide-mediated...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with connexin 43 (GJA1, P17302). Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:17761141 Connexin 43 confers resistance to hydrogen peroxide-mediated apoptosis.
GO:0004672 protein kinase activity	IDA PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	MARK AS OVER ANNOTATED	Summary: PMID:11096076 demonstrated ASK1 kinase activity. "Fas ligation activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK)." Correct but redundant with MAP3K activity. Reason: Correct but redundant with the more specific MAP kinase kinase kinase activity term. Supporting Evidence: PMID:11096076 Nov 28. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.
GO:0019904 protein domain specific binding	IPI PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	ACCEPT	Summary: PMID:11096076 demonstrated ASK1 interaction with glutaminyl-tRNA synthetase (QRS, P47897) involving catalytic domains. "The association involved the catalytic domains of the two enzymes." Reason: More informative than generic protein binding; demonstrates domain-specific interaction. Supporting Evidence: PMID:11096076 The association involved the catalytic domains of the two enzymes
GO:0032991 protein-containing complex	IMP PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	ACCEPT	Summary: ASK1 forms various protein complexes (signalosome, IRE1-TRAF2-ASK1 complex). This is a very general cellular component term. Reason: ASK1 forms multiple functionally important protein complexes; acceptable general annotation. Supporting Evidence: PMID:11096076 Nov 28. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.
GO:0034198 cellular response to amino acid starvation	IDA PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	KEEP AS NON CORE	Summary: PMID:11096076 demonstrated ASK1 activation under glutamine deprivation. "HeLa cells were susceptible to Fas-mediated apoptosis under the condition of glutamine deprivation. Fas ligation activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Gln-deprived cells." Reason: Amino acid starvation response is a specific stress context, not a core function. Supporting Evidence: PMID:11096076 Fas ligation activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase (SAPK)) in Gln-deprived cells but not in normal cells
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	KEEP AS NON CORE	Summary: PMID:11096076 demonstrated ASK1 effects on transcription. "The ASK1 activity was inhibited by the interaction with QRS as determined by in vitro kinase and transcription assays." This reflects downstream effects of JNK/p38 activation. Reason: Transcriptional effects are downstream consequences of JNK/p38 activation, not direct ASK1 function. Supporting Evidence: PMID:11096076 Nov 28. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.
GO:0051403 stress-activated MAPK cascade	IDA PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	ACCEPT	Summary: ASK1 is a key activator of stress-activated MAPK cascades (JNK and p38). This broader term encompasses both pathways. Reason: Stress-activated MAPK cascade is a core function of ASK1. Supporting Evidence: PMID:11096076 Nov 28. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.
GO:1990604 IRE1-TRAF2-ASK1 complex	IDA PMID:12050113 ASK1 is essential for endoplasmic reticulum stress-induced n...	ACCEPT	Summary: PMID:12050113 demonstrated formation of IRE1-TRAF2-ASK1 complex during ER stress. "ER stress activates ASK1 through formation of an IRE1-TRAF2-ASK1 complex." This is a key functional complex for ASK1. Reason: IRE1-TRAF2-ASK1 complex is a well-characterized functional complex essential for ER stress signaling. Supporting Evidence: PMID:12050113 ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex
GO:1990604 IRE1-TRAF2-ASK1 complex	IDA PMID:23000344 Ursolic acid induces ER stress response to activate ASK1-JNK...	ACCEPT	Summary: PMID:23000344 also demonstrated IRE1-TRAF2-ASK1 complex formation. Duplicate with different evidence source. Reason: Additional experimental support for IRE1-TRAF2-ASK1 complex. Supporting Evidence: PMID:23000344 Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation
GO:0046330 positive regulation of JNK cascade	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on ortholog. Core function supported by direct evidence in other annotations. Reason: Core function with support from multiple sources.
GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on ortholog. Core function supported by direct evidence in other annotations. Reason: Core function with support from multiple sources.
GO:0034976 response to endoplasmic reticulum stress	IMP PMID:23000344 Ursolic acid induces ER stress response to activate ASK1-JNK...	ACCEPT	Summary: PMID:23000344 demonstrated ASK1 involvement in ER stress response. "ursolic acid induces a significant ER stress response...ER stress inhibitor salubrinal...diminishes ursolic acid-induced anti-T24 cell effects." Reason: ER stress response is a core function with experimental evidence. Supporting Evidence: PMID:23000344 ursolic acid induces a significant ER stress response in cultured human bladder cancer T24 cells
GO:1902911 protein kinase complex	IDA PMID:15983381 Interaction of DJ-1 with Daxx inhibits apoptosis signal-regu...	ACCEPT	Summary: ASK1 forms the signalosome complex with various partners. This is a fairly general cellular component annotation. Reason: ASK1 forms protein kinase complexes as part of its signaling function. Supporting Evidence: PMID:15983381 Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death.
GO:0005515 protein binding	IPI PMID:17389591 RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site ...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with DAB2IP/AIP1 (Q5VWQ8). Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:17389591 2007 Mar 27. RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for tumor necrosis factor-induced ASK1-JNK/p38 activation.
GO:0005829 cytosol	TAS Reactome:R-HSA-3225851	ACCEPT	Summary: Reactome pathway "ROS oxidize thioredoxin and activate MAP3K5" places ASK1 in cytosol. Acceptable localization annotation. Reason: Cytosolic localization is well-documented.
GO:0005829 cytosol	TAS Reactome:R-HSA-3228469	ACCEPT	Summary: Reactome pathway places ASK1 in cytosol. Duplicate acceptable. Reason: Cytosolic localization is well-documented.
GO:0005829 cytosol	TAS Reactome:R-NUL-3299417	ACCEPT	Summary: Reactome pathway places ASK1 in cytosol. Duplicate acceptable. Reason: Cytosolic localization is well-documented.
GO:0005515 protein binding	IPI PMID:12556535 Type 1 insulin-like growth factor receptor (IGF-IR) signalin...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with IGF1R (P08069). IGF1R signaling inhibits ASK1. Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:12556535 2003 Jan 28. Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1).
GO:0000165 MAPK cascade	IDA PMID:21771788 Positive regulation of apoptosis signal-regulating kinase 1 ...	ACCEPT	Summary: PMID:21771788 demonstrated ASK1 involvement in MAPK cascade signaling. "ZPR9...positively regulated ASK1-mediated signaling to both JNK and p38 kinases." Reason: MAPK cascade is a core function with experimental evidence. Supporting Evidence: PMID:21771788 Ectopic expression of wild-type ZPR9, but not an S314A/T318A mutant, stimulated ASK1 kinase activity and positively regulated ASK1-mediated signaling to both JNK and p38 kinases
GO:0004672 protein kinase activity	IDA PMID:21771788 Positive regulation of apoptosis signal-regulating kinase 1 ...	MARK AS OVER ANNOTATED	Summary: PMID:21771788 demonstrated ASK1 kinase activity. "Ectopic expression of wild-type ZPR9...stimulated ASK1 kinase activity." Correct but redundant with MAP3K activity. Reason: Correct but redundant with more specific MAP3K activity term. Supporting Evidence: PMID:21771788 2011 Jul 19. Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein.
GO:0007254 JNK cascade	IDA PMID:21771788 Positive regulation of apoptosis signal-regulating kinase 1 ...	ACCEPT	Summary: PMID:21771788 demonstrated ASK1 activation of JNK cascade. Core function with experimental evidence. Reason: JNK cascade is a core function. Supporting Evidence: PMID:21771788 2011 Jul 19. Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein.
GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress	IDA PMID:21771788 Positive regulation of apoptosis signal-regulating kinase 1 ...	ACCEPT	Summary: PMID:21771788 demonstrated ASK1 involvement in oxidative stress-induced apoptosis. "ZPR9 functionally stimulated...H(2)O(2)-mediated apoptosis in a phosphorylation-dependent manner." Reason: Core function with experimental evidence. Supporting Evidence: PMID:21771788 ZPR9 functionally stimulated ASK1-induced AP-1 transcriptional activity as well as H(2)O(2)-mediated apoptosis
GO:0043065 positive regulation of apoptotic process	IDA PMID:21771788 Positive regulation of apoptosis signal-regulating kinase 1 ...	ACCEPT	Summary: PMID:21771788 demonstrated ASK1 pro-apoptotic function. Core function with experimental evidence. Reason: Pro-apoptotic function is well-documented. Supporting Evidence: PMID:21771788 2011 Jul 19. Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein.
GO:0070301 cellular response to hydrogen peroxide	IDA PMID:20674765 Protein phosphatase with EF-hand domains 2 (PPEF2) is a pote...	ACCEPT	Summary: PMID:20674765 demonstrated ASK1 response to H2O2. "In COS-7 or HEK 293A cells treated with H(2)O(2), expression of PPEF2 abrogated sustained activation of p38 and one of the JNK p46 isoforms." ASK1 is activated by hydrogen peroxide. Reason: Hydrogen peroxide (ROS) response is a well-documented activation mechanism for ASK1. Supporting Evidence: PMID:20674765 PPEF2 efficiently suppressed H(2)O(2)-induced activation of ASK1
GO:0019903 protein phosphatase binding	IPI PMID:11959862 Scaffold role of a mitogen-activated protein kinase phosphat...	ACCEPT	Summary: PMID:11959862 demonstrated ASK1 interaction with SKRP1 (a MAPK phosphatase). Acceptable molecular function annotation. Reason: ASK1 binds multiple protein phosphatases for regulation. Supporting Evidence: PMID:11959862 2002 Apr 16. Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway.
GO:0000165 MAPK cascade	IDA PMID:17210579 Apoptosis signal-regulating kinase (ASK) 2 functions as a mi...	ACCEPT	Summary: PMID:17210579 demonstrated ASK1-ASK2 complex functions in MAPK cascade. Core function. Reason: MAPK cascade is a core function. Supporting Evidence: PMID:17210579 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
GO:0000287 magnesium ion binding	IDA PMID:17210579 Apoptosis signal-regulating kinase (ASK) 2 functions as a mi...	ACCEPT	Summary: Kinases require Mg2+ as cofactor. UniProt lists "Mg(2+)" as cofactor. Legitimate molecular function annotation. Reason: Magnesium ion binding is required for kinase catalytic activity. Supporting Evidence: PMID:17210579 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:17210579 Apoptosis signal-regulating kinase (ASK) 2 functions as a mi...	ACCEPT	Summary: PMID:17210579 demonstrated ASK1 MAP3K activity. "ASK2 also functions as a MAP3K only in a heteromeric complex with ASK1." Core function. Reason: MAP3K activity is the core molecular function. Supporting Evidence: PMID:17210579 ASK2, a highly related serine/threonine kinase to ASK1, also functions as a MAP3K only in a heteromeric complex with ASK1
GO:0005524 ATP binding	IDA PMID:17210579 Apoptosis signal-regulating kinase (ASK) 2 functions as a mi...	ACCEPT	Summary: PMID:17210579 provides experimental evidence for ASK1 ATP binding as part of kinase activity studies. Reason: ATP binding is essential for kinase function. Supporting Evidence: PMID:17210579 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
GO:0042803 protein homodimerization activity	IDA PMID:11920685 Activation of apoptosis signal-regulating kinase 1 by the st...	ACCEPT	Summary: PMID:11920685 demonstrated ASK1 homodimerization. "ASK1 appears to form a silent homo-oligomer through its C-terminal coiled-coil region in non-stressed cells." This is more specific than identical protein binding. Reason: Homodimerization is a well-documented property essential for ASK1 regulation. Supporting Evidence: PMID:11920685 ASK1 appears to form a silent homo-oligomer through its C-terminal coiled-coil region in non-stressed cells
GO:0005515 protein binding	IPI PMID:14761963 Positive regulation of apoptosis signal-regulating kinase 1 ...	MARK AS OVER ANNOTATED	Summary: This annotation refers to interaction with TPD52L1 (Q16890). Protein binding is uninformative. Reason: Protein binding is too general and uninformative. Supporting Evidence: PMID:14761963 2004 Feb 4. Positive regulation of apoptosis signal-regulating kinase 1 by hD53L1.
GO:0000165 MAPK cascade	TAS PMID:8974401 Induction of apoptosis by ASK1, a mammalian MAPKKK that acti...	ACCEPT	Summary: The original ASK1 discovery paper (PMID:8974401) identified it as a MAPKKK. Core function with traceable author statement. Reason: Core function documented in original discovery paper. Supporting Evidence: PMID:8974401 A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified
GO:0004709 MAP kinase kinase kinase activity	TAS PMID:8974401 Induction of apoptosis by ASK1, a mammalian MAPKKK that acti...	ACCEPT	Summary: Original discovery paper identified ASK1 as a MAPKKK. Core function. Reason: Core function documented in original discovery paper. Supporting Evidence: PMID:8974401 A MAP kinase kinase kinase (MAPKKK), termed ASK1
GO:0097190 apoptotic signaling pathway	TAS PMID:8974401 Induction of apoptosis by ASK1, a mammalian MAPKKK that acti...	ACCEPT	Summary: PMID:8974401 demonstrated "Overexpression of ASK1 induced apoptotic cell death." Core function. Reason: Apoptotic signaling is well-documented in original discovery paper. Supporting Evidence: PMID:8974401 Overexpression of ASK1 induced apoptotic cell death

Core Functions

ASK1 functions as a serine/threonine MAP3K (EC 2.7.11.25) that directly phosphorylates and activates MAP2K4/MKK4, MAP2K7/MKK7 (JNK pathway), MAP2K3/MKK3, and MAP2K6/MKK6 (p38 pathway).

Molecular Function:

MAP kinase kinase kinase activity

ASK1 specifically activates the JNK pathway by phosphorylating MKK4 and MKK7.

Molecular Function:

JUN kinase kinase kinase activity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

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

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

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

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:8974401

Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.

ASK1 was identified as a MAP kinase kinase kinase (MAPKKK) that activates SEK1/MKK4 and MKK3/MKK6

"A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6)"
Overexpression of ASK1 induces apoptotic cell death

"Overexpression of ASK1 induced apoptotic cell death"
ASK1 is activated by TNF-alpha

"ASK1 was activated in cells treated with tumor necrosis factor-alpha (TNF-alpha)"

PMID:11096076

Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.

ASK1 is activated during glutamine deprivation

"Fas ligation activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase (SAPK)) in Gln-deprived cells but not in normal cells"
QRS interacts with ASK1 via catalytic domains to inhibit ASK1 activity

"The association involved the catalytic domains of the two enzymes. The ASK1 activity was inhibited by the interaction with QRS"

PMID:11154276

Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1.

PMID:11298454

HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell.

PMID:11495919

Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm.

PMID:11920685

Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer.

ASK1 forms homo-oligomers through C-terminal coiled-coil region

"ASK1 appears to form a silent homo-oligomer through its C-terminal coiled-coil region in non-stressed cells"
Thr845 (Thr838 in human) phosphorylation is essential for activation

"phosphorylation of Thr845 at the activation loop is essential for ASK1 to be activated by H2O2"
Oxidative stress triggers conformational change and autophosphorylation

"Following H2O2 treatment, pre-existing ASK1 oligomer undergoes conformational change and creates a new interface within an oligomer, which ultimately leads to trans-autophosphorylation of Thr845"

PMID:11959862

Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway.

ASK1 interacts with SKRP1 (MKP)

"SKRP1 also interacted with the MAPKKK, apoptosis signal-regulating kinase 1 (ASK1)"
SKRP1 enhances activation of MKK7 by ASK1

"SKRP1 expression increased the ASK1-MKK7 complexes in a dose-dependent manner and specifically enhanced the activation of MKK7 by ASK1"

PMID:12050113

ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.

ER stress activates ASK1 through IRE1-TRAF2-ASK1 complex formation

"ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex"
ASK1-/- neurons are defective in ER stress-induced JNK activation and cell death

"ASK1(-/-) primary neurons are defective in polyQ-, proteasome inhibitor-, and ER stress-induced JNK activation and cell death"

PMID:12556535

Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1).

PMID:12813029

AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3.

PMID:14557248

Identification of a novel antiapoptotic protein that antagonizes ASK1 and CAD activities.

PMID:14761963

Positive regulation of apoptosis signal-regulating kinase 1 by hD53L1.

PMID:15023544

Interaction of apoptosis signal-regulating kinase 1 with isoforms of 14-3-3 proteins.

PMID:15246877

S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system activates apoptosis signal-regulating kinase 1.

PMID:15983381

Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death.

DJ-1 protects against oxidative stress by sequestering Daxx

"wild-type DJ-1 sequesters Daxx in the nucleus, prevents it from gaining access to the cytoplasm"
Daxx activates ASK1 when in cytoplasm

"from binding to and activating its effector kinase apoptosis signal-regulating kinase 1"
ASK1-/- primary neurons are defective in stress-induced cell death

"the regulated sequestration of Daxx in the nucleus and keeping apoptosis signal-regulating kinase 1 activation in check is a critical mechanism by which DJ-1 exerts its cytoprotective function"

PMID:16449798

Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice.

PMID:16636664

Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals.

PMID:16648474

Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth.

PMID:17210579

Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.

ASK1 forms heteromeric complex with ASK2

"ASK2, a highly related serine/threonine kinase to ASK1, also functions as a MAP3K only in a heteromeric complex with ASK1"
ASK2 requires ASK1 for stability and MAP3K function

"endogenous ASK2 was constitutively degraded in ASK1-deficient cells, suggesting that ASK1 is required for the stability of ASK2"
ASK2 activates ASK1 by direct phosphorylation

"ASK2 was found to activate ASK1 by direct phosphorylation"

PMID:17389591

RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for tumor necrosis factor-induced ASK1-JNK/p38 activation.

PMID:17700517

G1 to S phase transition protein 1 induces apoptosis signal-regulating kinase 1 activation by dissociating 14-3-3 from ASK1.

PMID:17761141

Connexin 43 confers resistance to hydrogen peroxide-mediated apoptosis.

PMID:17937911

Structural and functional characterization of the human protein kinase ASK1.

ASK1 catalytic domain forms tight dimer (Kd ~0.2 uM)

"Sedimentation velocity measurements led to the determination of an apparent sedimentation coefficient corrected for water at 20°C, s20,w0, of 4.518 S, as well as the determination of a protein molecular weight of 66 kDa, which is in excellent agreement with the expected mass of an ASK1 catalytic domain dimer"
Autophosphorylation at Thr813, Thr838, Thr842 regulates signaling

"Reporter gene assays showed that all three identified in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate ASK1 signaling"
Crystal structure solved in complex with staurosporine

"Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine"

PMID:19590015

Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1.

PMID:19782076

A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex.

PMID:19805025

CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1.

PMID:19935702

Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome.

PMID:20674765

Protein phosphatase with EF-hand domains 2 (PPEF2) is a potent negative regulator of apoptosis signal regulating kinase-1 (ASK1).

PPEF2 interacts with and negatively regulates ASK1

"We identify human PPEF2 as a novel interacting partner and a negative regulator of ASK1"
PPEF2 suppresses H2O2-induced ASK1 activation

"PPEF2 efficiently suppressed H(2)O(2)-induced activation of ASK1"
ASK1 activation leads to caspase-3 cleavage

"prevented ASK1-dependent caspase-3 cleavage and activation"

PMID:21496457

Stabilization of the survival motor neuron protein by ASK1.

PMID:21771788

Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein.

ZPR9 is a positive regulator of ASK1

"ZPR9 was found to physically interact with apoptosis signal-regulating kinase 1 (ASK1)"
ZPR9 stimulates ASK1-mediated JNK and p38 signaling

"Ectopic expression of wild-type ZPR9, but not an S314A/T318A mutant, stimulated ASK1 kinase activity and positively regulated ASK1-mediated signaling to both JNK and p38 kinases"
ZPR9 destabilizes ASK1-Trx and ASK1-14-3-3 complexes

"by destabilizing complex formation between ASK1 and its negative regulators, Trx and 14-3-3"

PMID:22095282

Arginine methylation-dependent regulation of ASK1 signaling by PRMT1.

PMID:22609355

Microspherule protein 2 associates with ASK1 and acts as a negative regulator of stress-induced ASK1 activation.

PMID:23000344

Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells.

ER stress induces IRE1-TRAF2-ASK1 complex formation

"Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling"
ASK1-JNK signaling promotes apoptosis in response to ER stress

"ursolic acid induces a significant ER stress response in cultured human bladder cancer T24 cells"

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:25852190

Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.

PMID:26095851

Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1.

CypA binds ASK1 and negatively regulates its function

"CypA regulates apoptosis signaling-regulating kinase 1 (ASK1) through its direct binding"
CypA negatively regulates ASK1 Ser966 phosphorylation

"CypA negatively regulates phosphorylation of ASK1 at Ser966"
ASK1 induces caspase-3 activation and apoptosis

"ASK1 is known to induce caspase-3 activation and apoptosis"

PMID:28514442

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

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

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

PMID:35271311

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

PMID:9743501

Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx.

Reactome:R-HSA-2559583

Cellular Senescence

Reactome:R-HSA-3225851

ROS oxidize thioredoxin and activate MAP3K5

Reactome:R-HSA-3228469

MAP3K5 phosphorylates MKK3 and MKK6

Reactome:R-NUL-3299417

MAP3K5 (ASK1) phosphorylates Map2k4(Sek1)

PMID:11003656

Inhibition of Daxx-mediated apoptosis by heat shock protein 27.

HSP27 prevents interaction of Daxx with Ask1, blocking Daxx-mediated apoptosis

"phosphorylated dimers of HSP27 interact with Daxx, a mediator of Fas-induced apoptosis, preventing the interaction of Daxx with both Ask1 and Fas and blocking Daxx-mediated apoptosis"

file:human/MAP3K5/MAP3K5-deep-research-falcon.md

Deep research on MAP3K5 function

📚 Additional Documentation

Deep Research Falcon

(MAP3K5-deep-research-falcon.md)

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organism: human
gene_id: MAP3K5
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uniprot_accession: Q99683
protein_description: 'RecName: Full=Mitogen-activated protein kinase kinase kinase
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5; Short=MEKK 5;'
gene_info: Name=MAP3K5; Synonyms=ASK1, MAPKKK5, MEKK5;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the protein kinase superfamily. STE Ser/Thr
protein_domains: DRHyd-ASK. (IPR046872); HisK-N-like. (IPR046873); Kinase-like_dom_sf.
(IPR011009); MAP3K_PH. (IPR043969); MAP3K_TRAF-bd. (IPR025136)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q99683
Protein Description: RecName: Full=Mitogen-activated protein kinase kinase kinase 5; EC=2.7.11.25 {ECO:0000269|PubMed:26095851}; AltName: Full=Apoptosis signal-regulating kinase 1; Short=ASK-1; AltName: Full=MAPK/ERK kinase kinase 5; Short=MEK kinase 5; Short=MEKK 5;
Gene Information: Name=MAP3K5; Synonyms=ASK1, MAPKKK5, MEKK5;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the protein kinase superfamily. STE Ser/Thr
Key Domains: DRHyd-ASK. (IPR046872); HisK-N-like. (IPR046873); Kinase-like_dom_sf. (IPR011009); MAP3K_PH. (IPR043969); MAP3K_TRAF-bd. (IPR025136)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "MAP3K5" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'MAP3K5' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene MAP3K5 (gene ID: MAP3K5, UniProt: Q99683) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q99683
Protein Description: RecName: Full=Mitogen-activated protein kinase kinase kinase 5; EC=2.7.11.25 {ECO:0000269|PubMed:26095851}; AltName: Full=Apoptosis signal-regulating kinase 1; Short=ASK-1; AltName: Full=MAPK/ERK kinase kinase 5; Short=MEK kinase 5; Short=MEKK 5;
Gene Information: Name=MAP3K5; Synonyms=ASK1, MAPKKK5, MEKK5;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the protein kinase superfamily. STE Ser/Thr
Key Domains: DRHyd-ASK. (IPR046872); HisK-N-like. (IPR046873); Kinase-like_dom_sf. (IPR011009); MAP3K_PH. (IPR043969); MAP3K_TRAF-bd. (IPR025136)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "MAP3K5" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene MAP3K5 (gene ID: MAP3K5, UniProt: Q99683) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
Objective 1 confirmed: Human MAP3K5 encodes apoptosis signal-regulating kinase 1 (ASK1; UniProt Q99683), a serine/threonine MAPKKK (EC 2.7.11.25) that activates the JNK and p38 modules. Core regulatory features and domains in recent literature align with the UniProt description, including a TRAF-binding region, thioredoxin-binding inhibitory interface, activation-loop Thr838, and a 14-3-3 regulatory site at Ser966 (Aug 2022; https://doi.org/10.1007/s11033-022-07783-6; 2024 structural overview) (lu2022theroleand pages 7-8, honzejkova2024structuralstudiesof pages 28-31).

Comprehensive research report: MAP3K5 (ASK1) in human

Key concepts and definitions with current understanding
Identity and catalytic role: ASK1 is a stress-responsive MAP3K that phosphorylates and activates MAP2Ks MKK4/7 and MKK3/6 to drive JNK and p38 MAPK cascades, respectively, mediating cellular responses to oxidative, ER, and inflammatory stress (2022 review) (lu2022theroleand pages 7-8). The kinase domain adopts the canonical bilobal fold; autophosphorylation at Thr838 in the activation loop is essential for activation (2024 structural notes) (honzejkova2024structuralstudiesof pages 28-31).
Activation mechanisms:
Redox/thioredoxin: Under basal conditions, cytosolic Trx1 and mitochondrial Trx2 bind ASK1 and keep it inactive; oxidative stress oxidizes Trx and promotes dissociation, allowing ASK1 oligomerization and activation (2022 review; 2024 structural/mechanistic overview) (lu2022theroleand pages 7-8, honzejkova2024structuralstudiesof pages 28-31).
TRAF-mediated signalosome: TRAF2/6 interact with ASK1 (residues ~384–655) to promote oligomerization and activation; this assembly integrates TNF-family signals and stress cues (2024 structural notes) (honzejkova2024structuralstudiesof pages 28-31).
ER-stress axis: IRE1α recruits TRAF2, which scaffolds ASK1 to form an IRE1α–TRAF2–ASK1 complex that activates JNK/p38 and apoptosis during chronic ER stress in ischemic brain models (Feb 2024; https://doi.org/10.1007/s10753-024-01989-5) (kang2024inhibitionofendoplasmic pages 7-9).
Post-translational regulation: Inhibitory 14-3-3 binding at phospho-Ser966 and AKT-mediated Ser83 phosphorylation restrain ASK1; activation involves autophosphorylation at Thr838 and other sites (2022; 2024 structural notes) (lu2022theroleand pages 7-8, honzejkova2024structuralstudiesof pages 28-31). Ubiquitination/deubiquitination and arginine methylation further tune stability and signaling output (2022) (lu2022theroleand pages 9-10).
Biophysical context: Intracellular pH modulates ASK1 condensation; pHi elevation enhances optogenetically induced ASK1 clustering and augments JNK signaling, linking biophysical state to stress-kinase output (Aug 2024; https://doi.org/10.1038/s41467-024-50638-w) (honzejkova2024structuralstudiesof pages 28-31).
Localization: ASK1 functions primarily in the cytosol but is functionally coupled to mitochondria via Trx2 and can assemble into stress-induced condensates/signalosomes. In tissues, ASK1 activation is detected in stressed hepatocytes and neurons, where it drives p38/JNK outputs (2024 mechanistic/structural; Feb 2024 hepatology and inflammation studies) (honzejkova2024structuralstudiesof pages 28-31, peng2024ask1p38axisinhibition pages 1-2, kang2024inhibitionofendoplasmic pages 7-9).
Recent developments and latest research (2023–2024)
Senescence and SASP: ASK1 is activated during cellular senescence and drives the SASP via p38, promoting expression of proinflammatory cytokines/chemokines. ASK1-deficient mice show impaired immune clearance of senescent cells and increased tumorigenesis; conversely, ASK1 deficiency attenuates age-associated p38 activation, inflammation, and glomerulosclerosis (Jun 2024; https://doi.org/10.1038/s42003-024-06386-0) (odawara2024apoptosissignalregulatingkinase pages 1-3).
Inflammasome/pyroptosis licensing: JNK signaling is biphasic; MAP3K5-containing complexes contribute to downstream steps of inflammasome activation. Inhibition of MAP3K5 after priming suppresses IL-1β release, propidium iodide uptake, and GSDMD processing, and MAP3K5/JNK2 complexes associate with GSDMD, implying a licensing role near GSDMD-dependent permeabilization (May 2023; conference report; https://doi.org/10.4049/jimmunol.210.supp.167.01) (bradfield2023biphasicjnksignaling pages 3-6).
Liver disease and oncology: In murine cholestatic and toxic fibrosis models, pharmacologic ASK1 inhibition (GS-444217) reduced phosphorylated p38, hepatocyte death, and fibrosis by up to ~50% in the short term, limited bridging fibrosis by ~25% in the long term, prevented progression to cirrhosis (portal pressure ~6.07 vs 8.53 mm Hg), and cut liver tumor number/size by ~50% after 44 weeks. Mechanistically, ASK1/p38 inhibition blocked the release of mitochondrial DAMPs (mtDNA) from dying hepatocytes (Feb 2024; https://doi.org/10.1097/hep.0000000000000801) (peng2024ask1p38axisinhibition pages 1-2, peng2024ask1p38axisinhibition pages 17-25).
Neuroinflammation/ischemia: Targeting the IRE1α–TRAF2–ASK1–JNK axis with ER-stress modulators and ASK1 inhibition reduced neuronal apoptosis in chronic cerebral hypoperfusion models (Feb 2024) (kang2024inhibitionofendoplasmic pages 7-9).
Structural and systems updates: Recent structural work consolidated the roles of NCC-mediated oligomerization, TRAF binding, TRX inhibitory binding, activation-loop Thr838, and 14-3-3/Ser966, while systems studies linked intracellular pH to ASK1 condensates and JNK/p38 output (2024) (honzejkova2024structuralstudiesof pages 28-31).
Current applications and real-world implementations
Clinical-stage ASK1 inhibitors: Selonsertib (GS-4997) has been evaluated in diabetic kidney disease (DKD) and NASH. Mechanistically, GS-4997 and related ASK1 inhibitors suppress ER-stress–ASK1–JNK/p38 signaling and apoptosis in preclinical models (2014–2015 trials registered; mechanistic 2024 ischemia study) (kang2024inhibitionofendoplasmic pages 7-9). A 2022 liver-disease review notes phase 2 efficacy signals and subsequent phase 3 programs in NASH, contextualizing lessons learned for indication selection and endpoints (Aug 2022) (lu2022theroleand pages 9-10). Preclinically, GS-444217 yields robust antifibrotic and anti-tumor effects in liver disease models (Feb 2024) (peng2024ask1p38axisinhibition pages 1-2, peng2024ask1p38axisinhibition pages 17-25).
Biomarker-guided development: Preclinical liver studies quantified reductions in mtDNA DAMPs, p21+ hepatocytes, serum ammonia, and portal pressure as pharmacodynamic readouts of ASK1 inhibition (Feb 2024) (peng2024ask1p38axisinhibition pages 1-2, peng2024ask1p38axisinhibition pages 17-25).
Drug discovery: Novel small-molecule chemotypes beyond selonsertib (e.g., benzoheterocyclic-substituted amides) are being developed, with sub-100 nM biochemical potency reported, supporting continued medicinal chemistry around ASK1 (Mar 2024; https://doi.org/10.1039/d3md00663h) (lu2022theroleand pages 9-10).
Expert opinions and analysis from authoritative sources
Mechanistic consensus: Authoritative reviews and structural analyses converge on ASK1 as a redox-gated stress MAP3K controlled by TRX, TRAFs, 14-3-3, and activation-loop autophosphorylation. This architecture enables integration of ROS, ER stress, and cytokine signaling to tune JNK/p38 outputs (2022 review; 2024 structural overview) (lu2022theroleand pages 7-8, honzejkova2024structuralstudiesof pages 28-31).
Therapeutic positioning: The 2024 hepatology study frames ASK1 inhibition as a means to prevent progression to cirrhosis/HCC by curbing hepatocyte DAMP release and fibrogenic signaling, advocating clinical reevaluation with appropriate endpoints and timing (Feb 2024) (peng2024ask1p38axisinhibition pages 1-2, peng2024ask1p38axisinhibition pages 17-25). Concurrently, the 2024 senescence paper proposes ASK1 as a SASP driver and potential target for age-related inflammatory conditions, while warning that inhibiting ASK1 could impair immune clearance of senescent cells and theoretically influence tumor surveillance (Jun 2024) (odawara2024apoptosissignalregulatingkinase pages 1-3).
Innate immunity: New data suggest ASK1-containing MAP3K complexes contribute to inflammasome effector stages, indicating that ASK1 modulation may affect pyroptotic responses and IL-1β release in myeloid cells (May 2023) (bradfield2023biphasicjnksignaling pages 3-6).
Relevant statistics and data from recent studies
Liver disease models with ASK1 inhibition (GS-444217):
Short-term therapy reduced hepatocyte death and fibrosis up to ~50%; blocked p38 phosphorylation and mtDNA release from hepatocytes (Feb 2024) (peng2024ask1p38axisinhibition pages 1-2).
Long-term therapy reduced bridging fibrosis by ~25%, decreased p21+ hepatocytes by 72%, serum ammonia by 46%, and portal pressure from 8.53 to 6.07 mm Hg; 44-week treatment reduced tumor number and size by ~50% (Feb 2024) (peng2024ask1p38axisinhibition pages 17-25).
Senescence/aging models: ASK1 deficiency diminished age-associated p38 activation and inflammation and attenuated glomerulosclerosis; ASK1 is required for efficient immune clearance of senescent hepatocytes, with deficiency increasing tumorigenesis (Jun 2024) (odawara2024apoptosissignalregulatingkinase pages 1-3).
ER-stress/ischemia: ER-stress blockade and ASK1 inhibition lowered IRE1α/TRAF2/ASK1–JNK pathway activation and neuronal apoptosis in chronic cerebral hypoperfusion models (Feb 2024) (kang2024inhibitionofendoplasmic pages 7-9).

Embedded summary table
| Category | Succinct facts | Key citations (first author, year) |
|---|---|---|
| Identity / verification | Human MAP3K5 (ASK1); serine/threonine MAPKKK (EC 2.7.11.25); contains kinase domain, TRAF‑binding region, TRX‑binding inhibitory interface, activation‑loop Thr838 and regulatory 14‑3‑3 site Ser966. | Honzejkova 2024, Lu 2022 (honzejkova2024structuralstudiesof pages 28-31, lu2022theroleand pages 7-8) |
| Catalytic activity & substrates | Phosphotransferase that phosphorylates MAP2Ks MKK4/7 → activates JNK and MKK3/6 → activates p38; canonical stress MAPK cascade node. | Lu 2022, Kang 2024 (lu2022theroleand pages 7-8, kang2024inhibitionofendoplasmic pages 7-9) |
| Activation / regulation mechanisms | Activated by ROS via dissociation from thioredoxin (Trx1/Trx2); oligomerization and signalosome assembly via TRAF2/6; IRE1α–TRAF2–ASK1 assembly in ER stress; inhibitory phosphorylation/14‑3‑3 binding (Ser966) and Akt Ser83; essential autophosphorylation at Thr838; regulated by ubiquitination/methylation and pH‑dependent condensate formation. | Honzejkova 2024, Lu 2022, Kang 2024, Bradfield 2023 (honzejkova2024structuralstudiesof pages 28-31, lu2022theroleand pages 7-8, kang2024inhibitionofendoplasmic pages 7-9, bradfield2023biphasicjnksignaling pages 3-6) |
| Subcellular localization | Predominantly cytosolic; mitochondrial association mediated via Trx2; recruited to stress‑induced condensates/signalosomes and reported in neuronal/synaptic compartments under stress. | Honzejkova 2024, Peng 2024, Odawara 2024 (honzejkova2024structuralstudiesof pages 28-31, peng2024ask1p38axisinhibition pages 1-2, odawara2024apoptosissignalregulatingkinase pages 1-3) |
| 2023–2024 key findings | ASK1 drives SASP and age‑associated inflammation; licenses inflammasome/pyroptosis via a MAP3K5–JNK–GSDMD axis; ASK1/p38 inhibition blocks hepatocyte mitochondrial DAMP release and suppresses progression to fibrosis, cirrhosis and HCC in preclinical models. | Odawara 2024, Bradfield 2023, Peng 2024 (odawara2024apoptosissignalregulatingkinase pages 1-3, bradfield2023biphasicjnksignaling pages 3-6, peng2024ask1p38axisinhibition pages 1-2) |
| Applications / therapeutics | Clinical‑stage ASK1 inhibitor selonsertib (GS‑4997) evaluated in NASH/DKD; preclinical ASK1 inhibitors (e.g., GS‑444217) show antifibrotic efficacy; ongoing discovery of new chemotypes and biomarker (proteomic) signatures to stratify responders. | Lu 2022, Peng 2024 (lu2022theroleand pages 9-10, peng2024ask1p38axisinhibition pages 1-2, peng2024ask1p38axisinhibition pages 17-25) |
| Representative quantitative data | Peng 2024 preclinical metrics: short‑term ASK1i reduced fibrosis up to ~50%; long‑term bridging fibrosis ~25% reduction; p21+ hepatocytes −72%; serum ammonia −46%; portal pressure 6.07 vs 8.53 mm Hg; 44‑wk ASK1i reduced tumor number/size ≈50%. Odawara 2024: ASK1 deficiency prevents age‑related p38 activation and attenuates glomerulosclerosis. | Peng 2024, Odawara 2024 (peng2024ask1p38axisinhibition pages 1-2, peng2024ask1p38axisinhibition pages 17-25, odawara2024apoptosissignalregulatingkinase pages 1-3) |

Table: Concise, evidence‑linked summary of MAP3K5/ASK1 covering identity, catalytic role, regulatory mechanisms, localization, 2023–2024 key findings, therapeutic applications, and representative quantitative data; useful as a rapid reference with direct context‑ID citations for follow‑up.

Methodological notes and limitations
- Clinical trials of selonsertib (DKD, NASH) provide translational context; our mechanistic claims about selonsertib rely on recent preclinical and disease-mechanism studies and on a 2022 clinical review (kang2024inhibitionofendoplasmic pages 7-9, lu2022theroleand pages 9-10). Where precise trial outcomes are needed, consult the trial publications/records directly; here we emphasized 2023–2024 primary research and high-quality reviews. The liver disease study (Hepatology, 2024) supplies quantitative preclinical metrics supporting antifibrotic and anti-tumor potential via ASK1/p38 axis inhibition (peng2024ask1p38axisinhibition pages 1-2, peng2024ask1p38axisinhibition pages 17-25).

Conclusion
Human MAP3K5/ASK1 is a redox- and stress-gated MAP3K integrating thioredoxin status, TRAF-scaffolded assemblies, and ER-stress signaling to activate JNK and p38. Recent work highlights its roles in SASP regulation, inflammasome effector licensing, and organ-specific pathology, with compelling preclinical evidence that ASK1 inhibition reduces hepatocyte DAMP release, fibrosis progression, and tumor burden. Together with evolving structural insights and medicinal chemistry, these data refine ASK1’s therapeutic positioning while underscoring context-dependent trade-offs in immunity and senescence biology (lu2022theroleand pages 7-8, peng2024ask1p38axisinhibition pages 1-2, odawara2024apoptosissignalregulatingkinase pages 1-3, kang2024inhibitionofendoplasmic pages 7-9, lu2022theroleand pages 9-10, peng2024ask1p38axisinhibition pages 17-25, bradfield2023biphasicjnksignaling pages 3-6, honzejkova2024structuralstudiesof pages 28-31).

References

(lu2022theroleand pages 7-8): Yining Lu, Yanning Liu, and Min Zheng. The role and regulation of apoptosis signal-regulated kinase 1 in liver disease. Molecular Biology Reports, 49:10905-10914, Aug 2022. URL: https://doi.org/10.1007/s11033-022-07783-6, doi:10.1007/s11033-022-07783-6. This article has 4 citations and is from a peer-reviewed journal.
(honzejkova2024structuralstudiesof pages 28-31): K Honzejková. Structural studies of selected protein complexes involved in signal transduction. Unknown journal, 2024.
(kang2024inhibitionofendoplasmic pages 7-9): Kai Kang, Shu-Hui Chen, Da-Peng Wang, and Feng Chen. Inhibition of endoplasmic reticulum stress improves chronic ischemic hippocampal damage associated with suppression of ire1α/traf2/ask1/jnk-dependent apoptosis. Inflammation, 47:1479-1490, Feb 2024. URL: https://doi.org/10.1007/s10753-024-01989-5, doi:10.1007/s10753-024-01989-5. This article has 12 citations and is from a peer-reviewed journal.
(lu2022theroleand pages 9-10): Yining Lu, Yanning Liu, and Min Zheng. The role and regulation of apoptosis signal-regulated kinase 1 in liver disease. Molecular Biology Reports, 49:10905-10914, Aug 2022. URL: https://doi.org/10.1007/s11033-022-07783-6, doi:10.1007/s11033-022-07783-6. This article has 4 citations and is from a peer-reviewed journal.
(peng2024ask1p38axisinhibition pages 1-2): Zhenwei Peng, Guangyan Wei, Pinzhu Huang, Heansika Matta, Wen Gao, Ping An, Shuangshuang Zhao, Yi Lin, Li Tan, Kahini Vaid, Disha Skelton-Badlani, Imad Nasser, Grant Budas, David Lopez, Li Li, David Breckenridge, Rob Myers, John McHutchison, Ming Kuang, and Yury V. Popov. Ask1/p38 axis inhibition blocks the release of mitochondrial “danger signals” from hepatocytes and suppresses progression to cirrhosis and liver cancer. Hepatology, 80:346-362, Feb 2024. URL: https://doi.org/10.1097/hep.0000000000000801, doi:10.1097/hep.0000000000000801. This article has 8 citations and is from a highest quality peer-reviewed journal.
(odawara2024apoptosissignalregulatingkinase pages 1-3): Takeru Odawara, Shota Yamauchi, and Hidenori Ichijo. Apoptosis signal-regulating kinase 1 promotes inflammation in senescence and aging. Communications Biology, Jun 2024. URL: https://doi.org/10.1038/s42003-024-06386-0, doi:10.1038/s42003-024-06386-0. This article has 20 citations and is from a peer-reviewed journal.
(bradfield2023biphasicjnksignaling pages 3-6): Clinton J Bradfield, Jonathan J Liang, Orna Ernst, Sinu P John, Jing Sun, Sundar Ganesan, Adriana A de Jesus, Clare E Bryant, Raphaela Goldbach-Mansky, and Iain D C Fraser. Biphasic jnk signaling reveals distinct map3k complexes licensing inflammasome formation and pyroptosis. The Journal of Immunology, 210:167.01-167.01, May 2023. URL: https://doi.org/10.4049/jimmunol.210.supp.167.01, doi:10.4049/jimmunol.210.supp.167.01. This article has 26 citations.
(peng2024ask1p38axisinhibition pages 17-25): Zhenwei Peng, Guangyan Wei, Pinzhu Huang, Heansika Matta, Wen Gao, Ping An, Shuangshuang Zhao, Yi Lin, Li Tan, Kahini Vaid, Disha Skelton-Badlani, Imad Nasser, Grant Budas, David Lopez, Li Li, David Breckenridge, Rob Myers, John McHutchison, Ming Kuang, and Yury V. Popov. Ask1/p38 axis inhibition blocks the release of mitochondrial “danger signals” from hepatocytes and suppresses progression to cirrhosis and liver cancer. Hepatology, 80:346-362, Feb 2024. URL: https://doi.org/10.1097/hep.0000000000000801, doi:10.1097/hep.0000000000000801. This article has 8 citations and is from a highest quality peer-reviewed journal.

Citations

lu2022theroleand pages 7-8
honzejkova2024structuralstudiesof pages 28-31
kang2024inhibitionofendoplasmic pages 7-9
lu2022theroleand pages 9-10
odawara2024apoptosissignalregulatingkinase pages 1-3
bradfield2023biphasicjnksignaling pages 3-6
https://doi.org/10.1007/s11033-022-07783-6;
https://doi.org/10.1007/s10753-024-01989-5
https://doi.org/10.1038/s41467-024-50638-w
https://doi.org/10.1038/s42003-024-06386-0
https://doi.org/10.4049/jimmunol.210.supp.167.01
https://doi.org/10.1097/hep.0000000000000801
https://doi.org/10.1039/d3md00663h
https://doi.org/10.1007/s11033-022-07783-6,
https://doi.org/10.1007/s10753-024-01989-5,
https://doi.org/10.1097/hep.0000000000000801,
https://doi.org/10.1038/s42003-024-06386-0,
https://doi.org/10.4049/jimmunol.210.supp.167.01,

📄 View Raw YAML

id: Q99683
gene_symbol: MAP3K5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: MAP3K5 (ASK1, Apoptosis signal-regulating kinase 1) is a 
  serine/threonine MAP kinase kinase kinase (EC 2.7.11.25) that functions as a 
  master regulator of cellular stress responses. It directly phosphorylates and 
  activates MAP2K4/MKK4 and MAP2K7/MKK7 (activating the JNK pathway) and 
  MAP2K3/MKK3 and MAP2K6/MKK6 (activating the p38 MAPK pathway). ASK1 is 
  activated by oxidative stress through dissociation from its inhibitor 
  thioredoxin, by ER stress via formation of the IRE1-TRAF2-ASK1 complex, and by
  TNF-alpha signaling via TRAF2/TRAF6-mediated signalosome formation. Activation
  requires autophosphorylation at Thr-838 in the activation loop. ASK1 is 
  negatively regulated by 14-3-3 protein binding at phospho-Ser966 and by 
  AKT-mediated phosphorylation at Ser83. The protein forms homodimers through 
  its C-terminal coiled-coil domain when inactive. ASK1 plays essential roles in
  stress-induced apoptosis, innate immune responses, and cellular senescence.
existing_annotations:
  - term:
      id: GO:0007254
      label: JNK cascade
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ASK1 is a well-established upstream activator of the JNK cascade.
        The original discovery paper (Ichijo et al., 1997, PMID:8974401) 
        demonstrated that ASK1 "activated two different subgroups of MAP kinase 
        kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn
        activated stress-activated protein kinase (SAPK, also known as JNK)." 
        Multiple subsequent studies confirm ASK1 involvement in JNK cascade 
        activation via MKK4/MKK7 phosphorylation. The IBA annotation is 
        phylogenetically supported and represents a core function.
      action: ACCEPT
      reason: JNK cascade involvement is the core function of ASK1. The IBA 
        annotation is well-supported by extensive literature showing ASK1 
        directly phosphorylates MKK4/MKK7 to activate JNK.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: A MAP kinase kinase kinase (MAPKKK), termed ASK1, was
            identified that activated two different subgroups of MAP kinase 
            kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6)
        - reference_id: file:human/MAP3K5/MAP3K5-deep-research-falcon.md
          supporting_text: See deep research file for comprehensive analysis
  - term:
      id: GO:0008631
      label: intrinsic apoptotic signaling pathway in response to oxidative 
        stress
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ASK1 is a key mediator of oxidative stress-induced apoptosis. 
        Under basal conditions, thioredoxin (TXN) binds to and inhibits ASK1. 
        Oxidative stress causes oxidation of thioredoxin, leading to its 
        dissociation from ASK1 and subsequent ASK1 activation. This mechanism is
        well-documented (PMID:9564042, PMID:10688666). The UniProt record 
        confirms "Mediates signaling for determination of cell fate such as 
        differentiation and survival. Plays a crucial role in the apoptosis 
        signal transduction pathway through mitochondria-dependent caspase 
        activation."
      action: ACCEPT
      reason: Oxidative stress-induced apoptotic signaling is a well-established
        core function of ASK1, mediated through thioredoxin dissociation and 
        JNK/p38 activation.
      supported_by:
        - reference_id: PMID:21771788
          supporting_text: ZPR9 functionally stimulated ASK1-induced AP-1 
            transcriptional activity as well as H(2)O(2)-mediated apoptosis
        - reference_id: PMID:26095851
          supporting_text: ASK1 is known to induce caspase-3 activation and 
            apoptosis
  - term:
      id: GO:0038066
      label: p38MAPK cascade
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ASK1 directly phosphorylates MKK3/MKK6 to activate the p38 MAPK 
        cascade. The original discovery paper (Ichijo et al., 1997, 
        PMID:8974401) identified ASK1 as activating "MKK3/MAPKK6 (or MKK6), 
        which in turn activated...p38 subgroups of MAP kinases." UniProt 
        confirms ASK1 "acts as an upstream activator of the MKK/JNK signal 
        transduction cascade and the p38 MAPK signal transduction cascade 
        through the phosphorylation and activation of several MAP kinase kinases
        like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7."
      action: ACCEPT
      reason: p38MAPK cascade activation is a core function of ASK1, parallel to
        JNK cascade activation, both representing the primary downstream outputs
        of this MAP3K.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: A MAP kinase kinase kinase (MAPKKK), termed ASK1, was
            identified that activated two different subgroups of MAP kinase 
            kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in 
            turn activated stress-activated protein kinase (SAPK, also known as 
            JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, 
            respectively
  - term:
      id: GO:0051402
      label: neuron apoptotic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ASK1 has been implicated in neuronal apoptosis, particularly in 
        context of polyglutamine diseases and neurodegeneration. PMID:12050113 
        demonstrated "ASK1(-/-) primary neurons are defective in polyQ-, 
        proteasome inhibitor-, and ER stress-induced JNK activation and cell 
        death." PMID:15983381 showed DJ-1 protects neurons by sequestering Daxx 
        and preventing ASK1 activation. While relevant to neuronal contexts, 
        this is a downstream consequence of ASK1 activation rather than a core 
        molecular function.
      action: KEEP_AS_NON_CORE
      reason: Neuronal apoptosis is a context-dependent outcome of ASK1 
        activation, particularly relevant in neurodegenerative disease. While 
        well-documented, it represents a downstream phenotypic consequence 
        rather than the core enzymatic function.
      supported_by:
        - reference_id: PMID:12050113
          supporting_text: ASK1(-/-) primary neurons are defective in polyQ-, 
            proteasome inhibitor-, and ER stress-induced JNK activation and cell
            death
        - reference_id: PMID:15983381
          supporting_text: wild-type DJ-1 sequesters Daxx in the nucleus, 
            prevents it from gaining access to the cytoplasm, from binding to 
            and activating its effector kinase apoptosis signal-regulating 
            kinase 1
  - term:
      id: GO:0070059
      label: intrinsic apoptotic signaling pathway in response to endoplasmic 
        reticulum stress
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ASK1 is essential for ER stress-induced apoptosis. PMID:12050113 
        demonstrated that "ER stress activates ASK1 through formation of an 
        IRE1-TRAF2-ASK1 complex" and "ASK1(-/-) primary neurons are defective 
        in...ER stress-induced JNK activation and cell death." PMID:23000344 
        confirmed "ursolic acid induces IRE1-TRAF2-ASK1 signaling complex 
        formation to activate pro-apoptotic ASK1-JNK signaling." This represents
        a core stress-response function.
      action: ACCEPT
      reason: ER stress-induced apoptotic signaling via the IRE1-TRAF2-ASK1 
        complex is a well-established core function of ASK1, essential for ER 
        stress responses.
      supported_by:
        - reference_id: PMID:12050113
          supporting_text: ER stress activates ASK 1 through formation of an 
            IRE1-TRAF2-ASK1 complex
        - reference_id: PMID:23000344
          supporting_text: Ursolic acid induces IRE1-TRAF2-ASK1 signaling 
            complex formation to activate pro-apoptotic ASK1-JNK signaling
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: MAP kinase kinase kinase activity is the defining molecular 
        function of ASK1. The original discovery (PMID:8974401) identified ASK1 
        as "a MAP kinase kinase kinase (MAPKKK)...that activated two different 
        subgroups of MAP kinase kinases (MAPKK)." UniProt assigns EC 2.7.11.25 
        with evidence from PMID:26095851. The structural study (PMID:17937911) 
        confirmed the kinase domain structure and activity.
      action: ACCEPT
      reason: MAP kinase kinase kinase activity is the core molecular function 
        of ASK1. This is the primary enzymatic activity of the protein.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: A MAP kinase kinase kinase (MAPKKK), termed ASK1, was
            identified that activated two different subgroups of MAP kinase 
            kinases (MAPKK)
        - reference_id: PMID:17937911
          supporting_text: ASK1 activates both the JNK and p38 pathways by 
            direct phosphorylation of MAP kinase kinases (MKKs)
  - term:
      id: GO:0000165
      label: MAPK cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: MAPK cascade involvement is correct but very general. ASK1 
        specifically activates the stress-activated MAPK cascades (JNK and p38),
        not the classical ERK pathway. The more specific annotations for JNK 
        cascade (GO:0007254) and p38MAPK cascade (GO:0038066) are preferred.
      action: ACCEPT
      reason: While correct and acceptable as a broader parent term, the more 
        specific JNK cascade and p38MAPK cascade annotations capture the actual 
        function better. This IEA annotation provides appropriate general 
        coverage.
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: ASK1 binds ATP as part of its kinase activity. However, this term
        is very general. The more specific term ATP binding (GO:0005524) is more
        informative for a kinase.
      action: MARK_AS_OVER_ANNOTATED
      reason: Nucleotide binding is technically correct but too general for a 
        kinase. ATP binding (GO:0005524) is more specific and informative.
  - term:
      id: GO:0002376
      label: immune system process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: ASK1 plays a role in innate immune responses. UniProt notes 
        "MAP3K5/ASK1 is required for the innate immune response, which is 
        essential for host defense against a wide range of pathogens." However, 
        this term is very broad.
      action: MODIFY
      reason: While ASK1 is involved in immune processes, this term is too 
        general. The more specific term "innate immune response" (GO:0045087) 
        better captures the role.
      proposed_replacement_terms:
        - id: GO:0045087
          label: innate immune response
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Protein kinase activity is correct but redundant with the more 
        specific MAP kinase kinase kinase activity (GO:0004709). ASK1 is 
        specifically a MAP3K, not a general protein kinase.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein kinase activity is technically correct but redundant with 
        the more specific MAP kinase kinase kinase activity. The more specific 
        term should be preferred.
  - term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: ASK1 is indeed a serine/threonine kinase, but this term is 
        redundant with MAP kinase kinase kinase activity (GO:0004709) which is 
        more specific. MAP3Ks are by definition serine/threonine kinases.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with the more specific MAP kinase kinase kinase activity
        term. MAP3Ks are serine/threonine kinases by definition.
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: This is a duplicate annotation for MAP kinase kinase kinase 
        activity from a different IEA source. The annotation is correct and 
        represents the core function.
      action: ACCEPT
      reason: Duplicate of the IBA annotation for the same term. Both are 
        correct and acceptable - duplicates are fine in GO annotations when from
        different sources.
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: ATP binding is essential for kinase function. PMID:17210579 
        demonstrated ASK1 ATP binding experimentally, and the crystal structure 
        (PMID:17937911) shows staurosporine bound in the ATP binding site.
      action: ACCEPT
      reason: ATP binding is required for kinase activity and is experimentally 
        validated by structural and biochemical studies.
      supported_by:
        - reference_id: PMID:17937911
          supporting_text: The hinge region connecting the two domains lines the
            catalytic ATP binding site, which is occupied by the ATP competitive
            inhibitor staurosporine
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ASK1 is primarily cytoplasmic. UniProt states "Cytoplasm" as 
        subcellular location. Multiple studies confirm cytoplasmic localization.
        PMID:26095851 demonstrates cytoplasmic localization. The more specific 
        term cytosol (GO:0005829) may be more accurate.
      action: ACCEPT
      reason: Cytoplasmic localization is correct and well-documented. This 
        broader term is acceptable alongside the more specific cytosol 
        annotations.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ASK1 localizes to the ER in the context of the IRE1-TRAF2-ASK1 
        complex during ER stress. UniProt notes "Interaction with 14-3-3 
        proteins alters the distribution of MAP3K5/ASK1 and restricts it to the 
        perinuclear endoplasmic reticulum region." This is a conditional 
        localization during ER stress responses.
      action: ACCEPT
      reason: ER localization is correct in the context of ER stress signaling 
        via the IRE1-TRAF2-ASK1 complex. This represents functional localization
        during stress responses.
      supported_by:
        - reference_id: PMID:12050113
          supporting_text: ER stress activates ASK 1 through formation of an 
            IRE1-TRAF2-ASK1 complex
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: ASK1 is intimately involved in apoptosis. The original paper 
        (PMID:8974401) demonstrated "Overexpression of ASK1 induced apoptotic 
        cell death." However, more specific apoptotic signaling pathway terms 
        better capture the role.
      action: ACCEPT
      reason: Apoptotic process involvement is a well-established function of 
        ASK1, though more specific terms like apoptotic signaling pathway better
        describe the mechanism.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: Overexpression of ASK1 induced apoptotic cell death
  - term:
      id: GO:0016301
      label: kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Kinase activity is correct but very general. More specific terms 
        (MAP kinase kinase kinase activity, protein kinase activity) are more 
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Too general; more specific kinase activity terms exist for ASK1.
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Transferase activity is technically correct (kinases are 
        phosphotransferases) but extremely general and uninformative for 
        annotation purposes.
      action: MARK_AS_OVER_ANNOTATED
      reason: Too general; more specific terms are available that better 
        describe ASK1 function.
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: ASK1 plays a role in innate immunity. UniProt states "MAP3K5/ASK1
        is required for the innate immune response, which is essential for host 
        defense against a wide range of pathogens." ASK1 knockout mice are 
        resistant to LPS-induced septic shock. This is a legitimate biological 
        process annotation.
      action: KEEP_AS_NON_CORE
      reason: Innate immune response is a documented function of ASK1 but 
        represents a downstream consequence of its stress-responsive kinase 
        activity rather than its core molecular function.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Kinases typically bind divalent metal ions (Mg2+) as cofactors. 
        UniProt lists Mg2+ as a cofactor. However, this general term is less 
        informative than the specific magnesium ion binding annotation.
      action: MODIFY
      reason: Metal ion binding is correct but too general. Magnesium ion 
        binding (GO:0000287) is more specific and appropriate.
      proposed_replacement_terms:
        - id: GO:0000287
          label: magnesium ion binding
  - term:
      id: GO:0106310
      label: protein serine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: ASK1 has protein serine kinase activity. UniProt lists the 
        catalytic activity as phosphorylating L-seryl-[protein] with EC 
        2.7.11.25. However, the more specific MAP kinase kinase kinase activity 
        term is preferred.
      action: MARK_AS_OVER_ANNOTATED
      reason: Correct but redundant with MAP kinase kinase kinase activity. 
        MAP3Ks phosphorylate serine/threonine residues by definition.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11003656
    review:
      summary: This protein binding annotation refers to interaction with Daxx 
        (Q9UER7). ASK1-Daxx interaction is functionally important for apoptosis 
        signaling. However, "protein binding" is uninformative - more specific 
        terms would be preferred.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative. The ASK1-Daxx 
        interaction has functional significance but generic protein binding does
        not capture the biological meaning.
      supported_by:
        - reference_id: PMID:11003656
          supporting_text: Inhibition of Daxx-mediated apoptosis by heat shock 
            protein 27.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11154276
    review:
      summary: This annotation refers to interaction with AKT1 (P31749). AKT1 
        phosphorylates ASK1 at Ser83 to inhibit its activity. This is a 
        regulatory interaction but "protein binding" is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general. The AKT1-ASK1 interaction 
        represents regulatory phosphorylation, not just binding.
      supported_by:
        - reference_id: PMID:11154276
          supporting_text: Akt phosphorylates and negatively regulates apoptosis
            signal-regulating kinase 1
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11298454
    review:
      summary: This annotation refers to interaction with HIV-1 Nef. UniProt 
        notes "HIV-1 Nef inhibits MAP3K5/ASK1 signaling." This represents viral 
        evasion mechanism, and protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general for annotation purposes, even 
        though the interaction is biologically significant.
      supported_by:
        - reference_id: PMID:11298454
          supporting_text: HIV-1 Nef inhibits ASK1-dependent death signalling 
            providing a potential mechanism for protecting the infected host 
            cell.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11495919
    review:
      summary: This annotation refers to Daxx interaction (Q9UER7), duplicate of
        PMID:11003656. Protein binding remains uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:11495919
          supporting_text: 2001 Aug 8. Apoptosis signal-regulating kinase 1 
            controls the proapoptotic function of death-associated protein 
            (Daxx) in the cytoplasm.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12813029
    review:
      summary: This annotation refers to interaction with DAB2IP/AIP1 (Q5VWQ8). 
        AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating 
        dissociation of ASK1 from its inhibitor 14-3-3. Functionally important 
        but protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:12813029
          supporting_text: AIP1 mediates TNF-alpha-induced ASK1 activation by 
            facilitating dissociation of ASK1 from its inhibitor 14-3-3.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14557248
    review:
      summary: Protein binding annotation from IntAct. Generic and 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:14557248
          supporting_text: Identification of a novel antiapoptotic protein that 
            antagonizes ASK1 and CAD activities.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15023544
    review:
      summary: This annotation refers to interaction with 14-3-3 proteins 
        (YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ, SFN). 14-3-3 binding at 
        phospho-Ser966 inhibits ASK1 activity. This is a critical regulatory 
        interaction but protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general. The 14-3-3 interaction is 
        functionally critical for ASK1 regulation.
      supported_by:
        - reference_id: PMID:15023544
          supporting_text: Interaction of apoptosis signal-regulating kinase 1 
            with isoforms of 14-3-3 proteins.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16449798
    review:
      summary: Protein binding annotation referencing 14-3-3 zeta. 
        Uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:16449798
          supporting_text: Thioredoxin-ASK1 complex levels regulate ROS-mediated
            p38 MAPK pathway activity in livers of aged and long-lived Snell 
            dwarf mice.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16636664
    review:
      summary: This annotation refers to interaction with GSTP1 (Q12933). GSTP1 
        regulates TRAF2-ASK1 signals. Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:16636664
          supporting_text: Apr 24. Human glutathione S-transferase P1-1 
            interacts with TRAF2 and regulates TRAF2-ASK1 signals.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16648474
    review:
      summary: This annotation refers to interaction with calcineurin regulatory
        subunit PPP3R1 (P63098). Calcineurin dephosphorylates ASK1 Ser966. 
        Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:16648474
          supporting_text: Direct interaction and reciprocal regulation between 
            ASK1 and calcineurin-NFAT control cardiomyocyte death and growth.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17210579
    review:
      summary: This annotation refers to interaction with ASK2/MAP3K6 (Q9WTR2 - 
        mouse). ASK1 forms heteromeric complexes with ASK2 that are important 
        for stress signaling. Protein binding is uninformative but the 
        interaction is functionally important.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general. ASK1-ASK2 heteromerization is 
        functionally important but not captured by generic protein binding.
      supported_by:
        - reference_id: PMID:17210579
          supporting_text: 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 
            2 functions as a mitogen-activated protein kinase kinase kinase in a
            heteromeric complex with ASK1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17700517
    review:
      summary: This annotation refers to interaction with 14-3-3 eta (Q04917). 
        Generic protein binding annotation.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:17700517
          supporting_text: Aug 20. G1 to S phase transition protein 1 induces 
            apoptosis signal-regulating kinase 1 activation by dissociating 
            14-3-3 from ASK1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19590015
    review:
      summary: This annotation refers to interaction with PGAM5 (Q96HS1). PGAM5 
        dephosphorylates and activates ASK1. Important regulatory interaction 
        but protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:19590015
          supporting_text: Mitochondrial phosphoglycerate mutase 5 uses 
            alternate catalytic activity as a protein serine/threonine 
            phosphatase to activate ASK1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19782076
    review:
      summary: This annotation refers to interaction with beta-arrestin 2 
        (ARRB2, P32121). ARRB2 serves as a scaffold for JNK3 activation. Protein
        binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:19782076
          supporting_text: Epub 2009 Sep 24. A scanning peptide array approach 
            uncovers association sites within the JNK/beta arrestin signalling 
            complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19805025
    review:
      summary: This annotation refers to interaction with thioredoxin (TXN, 
        P10599) and other proteins. TXN-ASK1 interaction is critical for ASK1 
        regulation. However, protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general. The TXN-ASK1 interaction is the 
        key regulatory mechanism for ASK1 but is not captured by generic protein
        binding.
      supported_by:
        - reference_id: PMID:19805025
          supporting_text: CIB1 functions as a Ca(2+)-sensitive modulator of 
            stress-induced signaling by targeting ASK1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19935702
    review:
      summary: Protein binding annotation from IntAct. Generic and 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:19935702
          supporting_text: Dual engagement of 14-3-3 proteins controls signal 
            relay from ASK2 to the ASK1 signalosome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21496457
    review:
      summary: This annotation refers to interaction with SMN (Q16637). Protein 
        binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:21496457
          supporting_text: 2011 Apr 9. Stabilization of the survival motor 
            neuron protein by ASK1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21771788
    review:
      summary: This annotation refers to interactions with TXN, 14-3-3, MAP2K3, 
        and ZPR9 demonstrated in PMID:21771788. These are functionally important
        interactions but protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:21771788
          supporting_text: 2011 Jul 19. Positive regulation of apoptosis 
            signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger 
            protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22609355
    review:
      summary: This annotation refers to interaction with MCRS1 (Q96EZ8). 
        Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:22609355
          supporting_text: Epub 2012 May 15. Microspherule protein 2 associates 
            with ASK1 and acts as a negative regulator of stress-induced ASK1 
            activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25241761
    review:
      summary: This annotation from proximity ligation assay data. Protein 
        binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:25241761
          supporting_text: Oct 9. Using an in situ proximity ligation assay to 
            systematically profile endogenous protein-protein interactions in a 
            pathway network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25852190
    review:
      summary: Protein binding annotation from kinase network analysis. 
        Uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:25852190
          supporting_text: Integrative analysis of kinase networks in 
            TRAIL-induced apoptosis provides a source of potential targets for 
            combination therapy.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: High-throughput interactome study. Protein binding is 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative for functional 
        annotation.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31980649
    review:
      summary: High-throughput interactome study. Protein binding is 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:31980649
          supporting_text: Extensive rewiring of the EGFR network in colorectal 
            cancer cells expressing transforming levels of KRAS(G13D).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: High-throughput neurodegenerative disease interactome study. 
        Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: High-throughput proteome-scale interactome study. Protein binding
        is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: OpenCell endogenous tagging study. Protein binding is 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
            of human cellular organization.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9743501
    review:
      summary: This annotation refers to interaction with Daxx (Q9UER7). 
        PMID:9743501 demonstrated "Activation of apoptosis signal-regulating 
        kinase 1 (ASK1) by the adapter protein Daxx." Functionally important but
        protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:9743501
          supporting_text: Activation of apoptosis signal-regulating kinase 1 
            (ASK1) by the adapter protein Daxx.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:17937911
    review:
      summary: ASK1 homodimerization is well-documented. PMID:17937911 
        demonstrated by analytical ultracentrifugation that "the ASK1 catalytic 
        domain is dimeric in solution" with "determination of a dissociation 
        constant (KD) of 0.22 +/- 0.2 microM." PMID:11920685 showed "ASK1 
        appears to form a silent homo-oligomer through its C-terminal 
        coiled-coil region." This is more informative than generic protein 
        binding.
      action: ACCEPT
      reason: Identical protein binding (homodimerization) is a well-documented 
        and functionally important property of ASK1. Homodimerization is 
        required for activation.
      supported_by:
        - reference_id: PMID:17937911
          supporting_text: Sedimentation velocity measurements led to the 
            determination of...a protein molecular weight of 66 kDa, which is in
            excellent agreement with the expected mass of an ASK1 catalytic 
            domain dimer
        - reference_id: PMID:11920685
          supporting_text: ASK1 appears to form a silent homo-oligomer through 
            its C-terminal coiled-coil region in non-stressed cells
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:19805025
    review:
      summary: Additional evidence for ASK1 homodimerization. Acceptable 
        duplicate annotation from different source.
      action: ACCEPT
      reason: Homodimerization is a well-documented property of ASK1.
      supported_by:
        - reference_id: PMID:19805025
          supporting_text: CIB1 functions as a Ca(2+)-sensitive modulator of 
            stress-induced signaling by targeting ASK1.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:9743501
    review:
      summary: Additional evidence for ASK1 homodimerization from early study. 
        Acceptable duplicate annotation from different source.
      action: ACCEPT
      reason: Homodimerization is a well-documented property of ASK1.
      supported_by:
        - reference_id: PMID:9743501
          supporting_text: Activation of apoptosis signal-regulating kinase 1 
            (ASK1) by the adapter protein Daxx.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: ASK1 binds multiple protein kinases including AKT1, PIM1, and 
        downstream MAP2Ks. This is more informative than generic protein binding
        but still fairly general for a kinase that both phosphorylates and is 
        phosphorylated by other kinases.
      action: ACCEPT
      reason: Protein kinase binding is a legitimate function given ASK1 
        interactions with MAP2Ks and upstream kinases.
  - term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: ASK1 is essential for ER stress responses via the IRE1-TRAF2-ASK1
        complex. PMID:12050113 demonstrated "ER stress activates ASK1" and 
        PMID:23000344 showed ER stress induces IRE1-TRAF2-ASK1 complex 
        formation. This is a core function.
      action: ACCEPT
      reason: Response to ER stress is a well-documented core function of ASK1.
      supported_by:
        - reference_id: PMID:12050113
          supporting_text: ER stress activates ASK 1 through formation of an 
            IRE1-TRAF2-ASK1 complex
  - term:
      id: GO:0038066
      label: p38MAPK cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Duplicate annotation for p38MAPK cascade from different evidence 
        source. Core function of ASK1.
      action: ACCEPT
      reason: p38MAPK cascade is a core function, duplicate from different 
        source is acceptable.
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: ASK1 overexpression induces apoptosis (PMID:8974401). 
        PMID:21771788 showed "ZPR9 functionally stimulated ASK1-induced AP-1 
        transcriptional activity as well as H(2)O(2)-mediated apoptosis." 
        Pro-apoptotic function is well-established.
      action: ACCEPT
      reason: Positive regulation of apoptosis is a well-documented function of 
        ASK1, representing a core downstream outcome of its kinase activity.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: Overexpression of ASK1 induced apoptotic cell death
  - term:
      id: GO:0045663
      label: positive regulation of myoblast differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: ASK1 has been implicated in cellular differentiation in some 
        contexts. UniProt notes ASK1 "may also promote differentiation and 
        survival" depending on context. This is not a core function but 
        represents context-dependent effects.
      action: KEEP_AS_NON_CORE
      reason: Myoblast differentiation is a context-dependent effect of ASK1 
        signaling, not a core function.
  - term:
      id: GO:0046330
      label: positive regulation of JNK cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: ASK1 positively regulates JNK cascade by phosphorylating 
        MKK4/MKK7. This is a core function.
      action: ACCEPT
      reason: Positive regulation of JNK cascade is a core function of ASK1.
  - term:
      id: GO:0051402
      label: neuron apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Duplicate annotation for neuron apoptotic process from different 
        source. Context-dependent function.
      action: KEEP_AS_NON_CORE
      reason: Neuron apoptosis is context-dependent, not core function.
  - term:
      id: GO:0070059
      label: intrinsic apoptotic signaling pathway in response to endoplasmic 
        reticulum stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Duplicate annotation for ER stress-induced apoptosis from 
        different source. Core function.
      action: ACCEPT
      reason: ER stress-induced apoptotic signaling is a core function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Cytosolic localization confirmed by immunofluorescence (HPA). 
        UniProt lists cytoplasm as subcellular location. PMID:26095851 confirms 
        cytoplasmic localization.
      action: ACCEPT
      reason: Cytosolic localization is well-documented for ASK1.
      supported_by:
        - reference_id: PMID:26095851
          supporting_text: Cyclophilin A (CypA), a member of the immunophilin 
            family, is predominantly localized in the cytoplasm
  - term:
      id: GO:0090398
      label: cellular senescence
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2559583
    review:
      summary: ASK1 is involved in cellular senescence via the oxidative stress 
        induced senescence pathway. Recent research (2024) confirms ASK1 drives 
        SASP via p38 during senescence. This is a legitimate biological process.
      action: KEEP_AS_NON_CORE
      reason: Cellular senescence is a downstream consequence of ASK1-mediated 
        stress signaling, not a core function.
  - term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3228469
    review:
      summary: Reactome pathway "MAP3K5 phosphorylates MKK3 and MKK6." This TAS 
        annotation confirms kinase activity. Redundant with MAP3K activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with more specific MAP kinase kinase kinase activity 
        term.
  - term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-3299417
    review:
      summary: Reactome pathway "MAP3K5 (ASK1) phosphorylates Map2k4(Sek1)." 
        Duplicate TAS annotation for kinase activity. Redundant with MAP3K 
        activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with more specific MAP kinase kinase kinase activity 
        term.
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: IDA
    original_reference_id: PMID:15983381
    review:
      summary: PMID:15983381 demonstrated ASK1 kinase activity. The paper states
        DJ-1 "prevents it from gaining access to the cytoplasm, from binding to 
        and activating its effector kinase apoptosis signal-regulating kinase 
        1." This confirms ASK1 kinase activity.
      action: ACCEPT
      reason: MAP3K activity is the core molecular function, experimentally 
        validated.
      supported_by:
        - reference_id: PMID:15983381
          supporting_text: We demonstrate that wild-type DJ-1 sequesters Daxx in
            the nucleus, prevents it from gaining access to the cytoplasm, from 
            binding to and activating its effector kinase apoptosis 
            signal-regulating kinase 1
  - term:
      id: GO:0046330
      label: positive regulation of JNK cascade
    evidence_type: IMP
    original_reference_id: PMID:23000344
    review:
      summary: PMID:23000344 demonstrated "ursolic acid induces IRE1-TRAF2-ASK1 
        signaling complex formation to activate pro-apoptotic ASK1-JNK 
        signaling." IMP evidence for JNK cascade activation.
      action: ACCEPT
      reason: Core function with experimental evidence.
      supported_by:
        - reference_id: PMID:23000344
          supporting_text: Ursolic acid induces IRE1-TRAF2-ASK1 signaling 
            complex formation to activate pro-apoptotic ASK1-JNK signaling
  - term:
      id: GO:0019903
      label: protein phosphatase binding
    evidence_type: IPI
    original_reference_id: PMID:20674765
    review:
      summary: PMID:20674765 demonstrated ASK1 interaction with PPEF2 
        phosphatase. "We identify human PPEF2 as a novel interacting partner and
        a negative regulator of ASK1." ASK1 also binds PP5/PPP5C. Phosphatase 
        binding is relevant for ASK1 regulation.
      action: ACCEPT
      reason: Protein phosphatase binding is a legitimate molecular function 
        annotation given ASK1 regulation by multiple phosphatases.
      supported_by:
        - reference_id: PMID:20674765
          supporting_text: We identify human PPEF2 as a novel interacting 
            partner and a negative regulator of ASK1
  - term:
      id: GO:0097190
      label: apoptotic signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:20674765
    review:
      summary: PMID:20674765 demonstrated "expression of PPEF2 abrogated 
        sustained activation of p38 and one of the JNK p46 isoforms, and 
        prevented ASK1-dependent caspase-3 cleavage and activation." This 
        confirms ASK1 involvement in apoptotic signaling.
      action: ACCEPT
      reason: Apoptotic signaling pathway is a well-documented function of ASK1.
      supported_by:
        - reference_id: PMID:20674765
          supporting_text: In COS-7 or HEK 293A cells treated with H(2)O(2), 
            expression of PPEF2 abrogated sustained activation of p38 and one of
            the JNK p46 isoforms, and prevented ASK1-dependent caspase-3 
            cleavage and activation
  - term:
      id: GO:0051402
      label: neuron apoptotic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation based on mouse ortholog. Mouse ASK1 knockout 
        neurons are resistant to stress-induced apoptosis (PMID:12050113). 
        Context-dependent.
      action: KEEP_AS_NON_CORE
      reason: Neuron apoptosis is context-dependent, not core function.
  - term:
      id: GO:0036480
      label: neuron intrinsic apoptotic signaling pathway in response to 
        oxidative stress
    evidence_type: IGI
    original_reference_id: PMID:15983381
    review:
      summary: PMID:15983381 studied DJ-1 interaction with Daxx and ASK1 in 
        context of Parkinson disease. Shows ASK1 involved in neuronal oxidative 
        stress-induced apoptosis. Very specific and context-dependent.
      action: KEEP_AS_NON_CORE
      reason: This is a highly specific context-dependent annotation for 
        neuronal apoptosis, not a core general function.
      supported_by:
        - reference_id: PMID:15983381
          supporting_text: Interaction of DJ-1 with Daxx inhibits apoptosis 
            signal-regulating kinase 1 activity and cell death.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22095282
    review:
      summary: PMID:22095282 demonstrated ASK1 interaction with TRAF2 and PRMT1.
        PRMT1 methylates ASK1 to inhibit its activation. Protein binding is 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:22095282
          supporting_text: Nov 18. Arginine methylation-dependent regulation of 
            ASK1 signaling by PRMT1.
  - term:
      id: GO:0007254
      label: JNK cascade
    evidence_type: IMP
    original_reference_id: PMID:22095282
    review:
      summary: PMID:22095282 demonstrated that PRMT1 "negatively regulates 
        MAP3K5 association with TRAF2, inhibiting MAP3K5 activation" of JNK. IMP
        evidence for JNK cascade involvement.
      action: ACCEPT
      reason: JNK cascade is a core function, supported by experimental 
        evidence.
      supported_by:
        - reference_id: PMID:22095282
          supporting_text: Nov 18. Arginine methylation-dependent regulation of 
            ASK1 signaling by PRMT1.
  - term:
      id: GO:0004706
      label: JUN kinase kinase kinase activity
    evidence_type: IDA
    original_reference_id: PMID:11959862
    review:
      summary: PMID:11959862 demonstrated ASK1 activates MKK7 which activates 
        JNK. "SKRP1 selectively formed the stable complexes with MKK7...SKRP1 
        also interacted with the MAPKKK, apoptosis signal-regulating kinase 1 
        (ASK1)... SKRP1 expression...specifically enhanced the activation of 
        MKK7 by ASK1." JNK kinase kinase kinase activity is more specific than 
        general MAP3K activity.
      action: ACCEPT
      reason: JUN kinase kinase kinase activity is a more specific term 
        capturing ASK1 activation of the JNK pathway via MKK4/MKK7.
      supported_by:
        - reference_id: PMID:11959862
          supporting_text: SKRP1 expression increased the ASK1-MKK7 complexes in
            a dose-dependent manner and specifically enhanced the activation of 
            MKK7 by ASK1
  - term:
      id: GO:0007254
      label: JNK cascade
    evidence_type: IDA
    original_reference_id: PMID:11959862
    review:
      summary: PMID:11959862 provides IDA evidence for ASK1 in JNK cascade via 
        ASK1-MKK7 interaction. Core function.
      action: ACCEPT
      reason: JNK cascade is a core function with direct experimental evidence.
      supported_by:
        - reference_id: PMID:11959862
          supporting_text: 2002 Apr 16. Scaffold role of a mitogen-activated 
            protein kinase phosphatase, SKRP1, for the JNK signaling pathway.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26095851
    review:
      summary: PMID:26095851 demonstrated ASK1 interaction with cyclophilin A 
        (PPIA). "CypA negatively regulates phosphorylation of ASK1 at Ser966." 
        Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:26095851
          supporting_text: Cyclophilin A regulates JNK/p38-MAPK signaling 
            through its physical interaction with ASK1.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:26095851
    review:
      summary: PMID:26095851 shows ASK1 cytoplasmic localization. Acceptable 
        localization annotation.
      action: ACCEPT
      reason: Cytoplasmic localization is well-documented.
      supported_by:
        - reference_id: PMID:26095851
          supporting_text: Cyclophilin A regulates JNK/p38-MAPK signaling 
            through its physical interaction with ASK1.
  - term:
      id: GO:0008631
      label: intrinsic apoptotic signaling pathway in response to oxidative 
        stress
    evidence_type: IDA
    original_reference_id: PMID:26095851
    review:
      summary: PMID:26095851 demonstrates ASK1 involvement in oxidative 
        stress-induced apoptosis. "ASK1 is known to induce caspase-3 activation 
        and apoptosis, and CypA inhibited ASK1-mediated apoptosis by decrease in
        caspase-3 activity under cellular stress conditions."
      action: ACCEPT
      reason: Core function with experimental evidence.
      supported_by:
        - reference_id: PMID:26095851
          supporting_text: ASK1 is known to induce caspase-3 activation and 
            apoptosis
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15246877
    review:
      summary: This annotation refers to interaction with thioredoxin (P10599). 
        TXN-ASK1 interaction is critical for regulation but protein binding is 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:15246877
          supporting_text: S-nitrosation of thioredoxin in the nitrogen 
            monoxide/superoxide system activates apoptosis signal-regulating 
            kinase 1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17761141
    review:
      summary: This annotation refers to interaction with connexin 43 (GJA1, 
        P17302). Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:17761141
          supporting_text: Connexin 43 confers resistance to hydrogen 
            peroxide-mediated apoptosis.
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IDA
    original_reference_id: PMID:11096076
    review:
      summary: PMID:11096076 demonstrated ASK1 kinase activity. "Fas ligation 
        activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun 
        N-terminal kinase (JNK)." Correct but redundant with MAP3K activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: Correct but redundant with the more specific MAP kinase kinase 
        kinase activity term.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: Nov 28. Glutamine-dependent antiapoptotic interaction
            of human glutaminyl-tRNA synthetase with apoptosis signal-regulating
            kinase 1.
  - term:
      id: GO:0019904
      label: protein domain specific binding
    evidence_type: IPI
    original_reference_id: PMID:11096076
    review:
      summary: PMID:11096076 demonstrated ASK1 interaction with glutaminyl-tRNA 
        synthetase (QRS, P47897) involving catalytic domains. "The association 
        involved the catalytic domains of the two enzymes."
      action: ACCEPT
      reason: More informative than generic protein binding; demonstrates 
        domain-specific interaction.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: The association involved the catalytic domains of the
            two enzymes
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IMP
    original_reference_id: PMID:11096076
    review:
      summary: ASK1 forms various protein complexes (signalosome, 
        IRE1-TRAF2-ASK1 complex). This is a very general cellular component 
        term.
      action: ACCEPT
      reason: ASK1 forms multiple functionally important protein complexes; 
        acceptable general annotation.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: Nov 28. Glutamine-dependent antiapoptotic interaction
            of human glutaminyl-tRNA synthetase with apoptosis signal-regulating
            kinase 1.
  - term:
      id: GO:0034198
      label: cellular response to amino acid starvation
    evidence_type: IDA
    original_reference_id: PMID:11096076
    review:
      summary: PMID:11096076 demonstrated ASK1 activation under glutamine 
        deprivation. "HeLa cells were susceptible to Fas-mediated apoptosis 
        under the condition of glutamine deprivation. Fas ligation activated 
        apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase 
        (JNK) in Gln-deprived cells."
      action: KEEP_AS_NON_CORE
      reason: Amino acid starvation response is a specific stress context, not a
        core function.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: Fas ligation activated apoptosis signal-regulating 
            kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as 
            stress-activated protein kinase (SAPK)) in Gln-deprived cells but 
            not in normal cells
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:11096076
    review:
      summary: PMID:11096076 demonstrated ASK1 effects on transcription. "The 
        ASK1 activity was inhibited by the interaction with QRS as determined by
        in vitro kinase and transcription assays." This reflects downstream 
        effects of JNK/p38 activation.
      action: KEEP_AS_NON_CORE
      reason: Transcriptional effects are downstream consequences of JNK/p38 
        activation, not direct ASK1 function.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: Nov 28. Glutamine-dependent antiapoptotic interaction
            of human glutaminyl-tRNA synthetase with apoptosis signal-regulating
            kinase 1.
  - term:
      id: GO:0051403
      label: stress-activated MAPK cascade
    evidence_type: IDA
    original_reference_id: PMID:11096076
    review:
      summary: ASK1 is a key activator of stress-activated MAPK cascades (JNK 
        and p38). This broader term encompasses both pathways.
      action: ACCEPT
      reason: Stress-activated MAPK cascade is a core function of ASK1.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: Nov 28. Glutamine-dependent antiapoptotic interaction
            of human glutaminyl-tRNA synthetase with apoptosis signal-regulating
            kinase 1.
  - term:
      id: GO:1990604
      label: IRE1-TRAF2-ASK1 complex
    evidence_type: IDA
    original_reference_id: PMID:12050113
    review:
      summary: PMID:12050113 demonstrated formation of IRE1-TRAF2-ASK1 complex 
        during ER stress. "ER stress activates ASK1 through formation of an 
        IRE1-TRAF2-ASK1 complex." This is a key functional complex for ASK1.
      action: ACCEPT
      reason: IRE1-TRAF2-ASK1 complex is a well-characterized functional complex
        essential for ER stress signaling.
      supported_by:
        - reference_id: PMID:12050113
          supporting_text: ER stress activates ASK 1 through formation of an 
            IRE1-TRAF2-ASK1 complex
  - term:
      id: GO:1990604
      label: IRE1-TRAF2-ASK1 complex
    evidence_type: IDA
    original_reference_id: PMID:23000344
    review:
      summary: PMID:23000344 also demonstrated IRE1-TRAF2-ASK1 complex 
        formation. Duplicate with different evidence source.
      action: ACCEPT
      reason: Additional experimental support for IRE1-TRAF2-ASK1 complex.
      supported_by:
        - reference_id: PMID:23000344
          supporting_text: Ursolic acid induces IRE1-TRAF2-ASK1 signaling 
            complex formation
  - term:
      id: GO:0046330
      label: positive regulation of JNK cascade
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation based on ortholog. Core function supported by 
        direct evidence in other annotations.
      action: ACCEPT
      reason: Core function with support from multiple sources.
  - term:
      id: GO:0070059
      label: intrinsic apoptotic signaling pathway in response to endoplasmic 
        reticulum stress
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation based on ortholog. Core function supported by 
        direct evidence in other annotations.
      action: ACCEPT
      reason: Core function with support from multiple sources.
  - term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    evidence_type: IMP
    original_reference_id: PMID:23000344
    review:
      summary: PMID:23000344 demonstrated ASK1 involvement in ER stress 
        response. "ursolic acid induces a significant ER stress response...ER 
        stress inhibitor salubrinal...diminishes ursolic acid-induced anti-T24 
        cell effects."
      action: ACCEPT
      reason: ER stress response is a core function with experimental evidence.
      supported_by:
        - reference_id: PMID:23000344
          supporting_text: ursolic acid induces a significant ER stress response
            in cultured human bladder cancer T24 cells
  - term:
      id: GO:1902911
      label: protein kinase complex
    evidence_type: IDA
    original_reference_id: PMID:15983381
    review:
      summary: ASK1 forms the signalosome complex with various partners. This is
        a fairly general cellular component annotation.
      action: ACCEPT
      reason: ASK1 forms protein kinase complexes as part of its signaling 
        function.
      supported_by:
        - reference_id: PMID:15983381
          supporting_text: Interaction of DJ-1 with Daxx inhibits apoptosis 
            signal-regulating kinase 1 activity and cell death.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17389591
    review:
      summary: This annotation refers to interaction with DAB2IP/AIP1 (Q5VWQ8). 
        Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:17389591
          supporting_text: 2007 Mar 27. RIP1-mediated AIP1 phosphorylation at a 
            14-3-3-binding site is critical for tumor necrosis factor-induced 
            ASK1-JNK/p38 activation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3225851
    review:
      summary: Reactome pathway "ROS oxidize thioredoxin and activate MAP3K5" 
        places ASK1 in cytosol. Acceptable localization annotation.
      action: ACCEPT
      reason: Cytosolic localization is well-documented.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3228469
    review:
      summary: Reactome pathway places ASK1 in cytosol. Duplicate acceptable.
      action: ACCEPT
      reason: Cytosolic localization is well-documented.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-3299417
    review:
      summary: Reactome pathway places ASK1 in cytosol. Duplicate acceptable.
      action: ACCEPT
      reason: Cytosolic localization is well-documented.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12556535
    review:
      summary: This annotation refers to interaction with IGF1R (P08069). IGF1R 
        signaling inhibits ASK1. Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:12556535
          supporting_text: 2003 Jan 28. Type 1 insulin-like growth factor 
            receptor (IGF-IR) signaling inhibits apoptosis signal-regulating 
            kinase 1 (ASK1).
  - term:
      id: GO:0000165
      label: MAPK cascade
    evidence_type: IDA
    original_reference_id: PMID:21771788
    review:
      summary: PMID:21771788 demonstrated ASK1 involvement in MAPK cascade 
        signaling. "ZPR9...positively regulated ASK1-mediated signaling to both 
        JNK and p38 kinases."
      action: ACCEPT
      reason: MAPK cascade is a core function with experimental evidence.
      supported_by:
        - reference_id: PMID:21771788
          supporting_text: Ectopic expression of wild-type ZPR9, but not an 
            S314A/T318A mutant, stimulated ASK1 kinase activity and positively 
            regulated ASK1-mediated signaling to both JNK and p38 kinases
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IDA
    original_reference_id: PMID:21771788
    review:
      summary: PMID:21771788 demonstrated ASK1 kinase activity. "Ectopic 
        expression of wild-type ZPR9...stimulated ASK1 kinase activity." Correct
        but redundant with MAP3K activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: Correct but redundant with more specific MAP3K activity term.
      supported_by:
        - reference_id: PMID:21771788
          supporting_text: 2011 Jul 19. Positive regulation of apoptosis 
            signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger 
            protein.
  - term:
      id: GO:0007254
      label: JNK cascade
    evidence_type: IDA
    original_reference_id: PMID:21771788
    review:
      summary: PMID:21771788 demonstrated ASK1 activation of JNK cascade. Core 
        function with experimental evidence.
      action: ACCEPT
      reason: JNK cascade is a core function.
      supported_by:
        - reference_id: PMID:21771788
          supporting_text: 2011 Jul 19. Positive regulation of apoptosis 
            signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger 
            protein.
  - term:
      id: GO:0008631
      label: intrinsic apoptotic signaling pathway in response to oxidative 
        stress
    evidence_type: IDA
    original_reference_id: PMID:21771788
    review:
      summary: PMID:21771788 demonstrated ASK1 involvement in oxidative 
        stress-induced apoptosis. "ZPR9 functionally 
        stimulated...H(2)O(2)-mediated apoptosis in a phosphorylation-dependent 
        manner."
      action: ACCEPT
      reason: Core function with experimental evidence.
      supported_by:
        - reference_id: PMID:21771788
          supporting_text: ZPR9 functionally stimulated ASK1-induced AP-1 
            transcriptional activity as well as H(2)O(2)-mediated apoptosis
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:21771788
    review:
      summary: PMID:21771788 demonstrated ASK1 pro-apoptotic function. Core 
        function with experimental evidence.
      action: ACCEPT
      reason: Pro-apoptotic function is well-documented.
      supported_by:
        - reference_id: PMID:21771788
          supporting_text: 2011 Jul 19. Positive regulation of apoptosis 
            signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger 
            protein.
  - term:
      id: GO:0070301
      label: cellular response to hydrogen peroxide
    evidence_type: IDA
    original_reference_id: PMID:20674765
    review:
      summary: PMID:20674765 demonstrated ASK1 response to H2O2. "In COS-7 or 
        HEK 293A cells treated with H(2)O(2), expression of PPEF2 abrogated 
        sustained activation of p38 and one of the JNK p46 isoforms." ASK1 is 
        activated by hydrogen peroxide.
      action: ACCEPT
      reason: Hydrogen peroxide (ROS) response is a well-documented activation 
        mechanism for ASK1.
      supported_by:
        - reference_id: PMID:20674765
          supporting_text: PPEF2 efficiently suppressed H(2)O(2)-induced 
            activation of ASK1
  - term:
      id: GO:0019903
      label: protein phosphatase binding
    evidence_type: IPI
    original_reference_id: PMID:11959862
    review:
      summary: PMID:11959862 demonstrated ASK1 interaction with SKRP1 (a MAPK 
        phosphatase). Acceptable molecular function annotation.
      action: ACCEPT
      reason: ASK1 binds multiple protein phosphatases for regulation.
      supported_by:
        - reference_id: PMID:11959862
          supporting_text: 2002 Apr 16. Scaffold role of a mitogen-activated 
            protein kinase phosphatase, SKRP1, for the JNK signaling pathway.
  - term:
      id: GO:0000165
      label: MAPK cascade
    evidence_type: IDA
    original_reference_id: PMID:17210579
    review:
      summary: PMID:17210579 demonstrated ASK1-ASK2 complex functions in MAPK 
        cascade. Core function.
      action: ACCEPT
      reason: MAPK cascade is a core function.
      supported_by:
        - reference_id: PMID:17210579
          supporting_text: 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 
            2 functions as a mitogen-activated protein kinase kinase kinase in a
            heteromeric complex with ASK1.
  - term:
      id: GO:0000287
      label: magnesium ion binding
    evidence_type: IDA
    original_reference_id: PMID:17210579
    review:
      summary: Kinases require Mg2+ as cofactor. UniProt lists "Mg(2+)" as 
        cofactor. Legitimate molecular function annotation.
      action: ACCEPT
      reason: Magnesium ion binding is required for kinase catalytic activity.
      supported_by:
        - reference_id: PMID:17210579
          supporting_text: 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 
            2 functions as a mitogen-activated protein kinase kinase kinase in a
            heteromeric complex with ASK1.
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: IDA
    original_reference_id: PMID:17210579
    review:
      summary: PMID:17210579 demonstrated ASK1 MAP3K activity. "ASK2 also 
        functions as a MAP3K only in a heteromeric complex with ASK1." Core 
        function.
      action: ACCEPT
      reason: MAP3K activity is the core molecular function.
      supported_by:
        - reference_id: PMID:17210579
          supporting_text: ASK2, a highly related serine/threonine kinase to 
            ASK1, also functions as a MAP3K only in a heteromeric complex with 
            ASK1
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IDA
    original_reference_id: PMID:17210579
    review:
      summary: PMID:17210579 provides experimental evidence for ASK1 ATP binding
        as part of kinase activity studies.
      action: ACCEPT
      reason: ATP binding is essential for kinase function.
      supported_by:
        - reference_id: PMID:17210579
          supporting_text: 2007 Jan 8. Apoptosis signal-regulating kinase (ASK) 
            2 functions as a mitogen-activated protein kinase kinase kinase in a
            heteromeric complex with ASK1.
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IDA
    original_reference_id: PMID:11920685
    review:
      summary: PMID:11920685 demonstrated ASK1 homodimerization. "ASK1 appears 
        to form a silent homo-oligomer through its C-terminal coiled-coil region
        in non-stressed cells." This is more specific than identical protein 
        binding.
      action: ACCEPT
      reason: Homodimerization is a well-documented property essential for ASK1 
        regulation.
      supported_by:
        - reference_id: PMID:11920685
          supporting_text: ASK1 appears to form a silent homo-oligomer through 
            its C-terminal coiled-coil region in non-stressed cells
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14761963
    review:
      summary: This annotation refers to interaction with TPD52L1 (Q16890). 
        Protein binding is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too general and uninformative.
      supported_by:
        - reference_id: PMID:14761963
          supporting_text: 2004 Feb 4. Positive regulation of apoptosis 
            signal-regulating kinase 1 by hD53L1.
  - term:
      id: GO:0000165
      label: MAPK cascade
    evidence_type: TAS
    original_reference_id: PMID:8974401
    review:
      summary: The original ASK1 discovery paper (PMID:8974401) identified it as
        a MAPKKK. Core function with traceable author statement.
      action: ACCEPT
      reason: Core function documented in original discovery paper.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: A MAP kinase kinase kinase (MAPKKK), termed ASK1, was
            identified
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: TAS
    original_reference_id: PMID:8974401
    review:
      summary: Original discovery paper identified ASK1 as a MAPKKK. Core 
        function.
      action: ACCEPT
      reason: Core function documented in original discovery paper.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: A MAP kinase kinase kinase (MAPKKK), termed ASK1
  - term:
      id: GO:0097190
      label: apoptotic signaling pathway
    evidence_type: TAS
    original_reference_id: PMID:8974401
    review:
      summary: PMID:8974401 demonstrated "Overexpression of ASK1 induced 
        apoptotic cell death." Core function.
      action: ACCEPT
      reason: Apoptotic signaling is well-documented in original discovery 
        paper.
      supported_by:
        - reference_id: PMID:8974401
          supporting_text: Overexpression of ASK1 induced apoptotic cell death
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000116
    title: Automatic Gene Ontology annotation based on Rhea mapping
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:8974401
    title: Induction of apoptosis by ASK1, a mammalian MAPKKK that activates 
      SAPK/JNK and p38 signaling pathways.
    findings:
      - statement: ASK1 was identified as a MAP kinase kinase kinase (MAPKKK) 
          that activates SEK1/MKK4 and MKK3/MKK6
        supporting_text: A MAP kinase kinase kinase (MAPKKK), termed ASK1, was 
          identified that activated two different subgroups of MAP kinase 
          kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6)
      - statement: Overexpression of ASK1 induces apoptotic cell death
        supporting_text: Overexpression of ASK1 induced apoptotic cell death
      - statement: ASK1 is activated by TNF-alpha
        supporting_text: ASK1 was activated in cells treated with tumor necrosis
          factor-alpha (TNF-alpha)
  - id: PMID:11096076
    title: Glutamine-dependent antiapoptotic interaction of human 
      glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.
    findings:
      - statement: ASK1 is activated during glutamine deprivation
        supporting_text: Fas ligation activated apoptosis signal-regulating 
          kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as 
          stress-activated protein kinase (SAPK)) in Gln-deprived cells but not 
          in normal cells
      - statement: QRS interacts with ASK1 via catalytic domains to inhibit ASK1
          activity
        supporting_text: The association involved the catalytic domains of the 
          two enzymes. The ASK1 activity was inhibited by the interaction with 
          QRS
  - id: PMID:11154276
    title: Akt phosphorylates and negatively regulates apoptosis 
      signal-regulating kinase 1.
    findings: []
  - id: PMID:11298454
    title: HIV-1 Nef inhibits ASK1-dependent death signalling providing a 
      potential mechanism for protecting the infected host cell.
    findings: []
  - id: PMID:11495919
    title: Apoptosis signal-regulating kinase 1 controls the proapoptotic 
      function of death-associated protein (Daxx) in the cytoplasm.
    findings: []
  - id: PMID:11920685
    title: Activation of apoptosis signal-regulating kinase 1 by the 
      stress-induced activating phosphorylation of pre-formed oligomer.
    findings:
      - statement: ASK1 forms homo-oligomers through C-terminal coiled-coil 
          region
        supporting_text: ASK1 appears to form a silent homo-oligomer through its
          C-terminal coiled-coil region in non-stressed cells
      - statement: Thr845 (Thr838 in human) phosphorylation is essential for 
          activation
        supporting_text: phosphorylation of Thr845 at the activation loop is 
          essential for ASK1 to be activated by H2O2
      - statement: Oxidative stress triggers conformational change and 
          autophosphorylation
        supporting_text: Following H2O2 treatment, pre-existing ASK1 oligomer 
          undergoes conformational change and creates a new interface within an 
          oligomer, which ultimately leads to trans-autophosphorylation of 
          Thr845
  - id: PMID:11959862
    title: Scaffold role of a mitogen-activated protein kinase phosphatase, 
      SKRP1, for the JNK signaling pathway.
    findings:
      - statement: ASK1 interacts with SKRP1 (MKP)
        supporting_text: SKRP1 also interacted with the MAPKKK, apoptosis 
          signal-regulating kinase 1 (ASK1)
      - statement: SKRP1 enhances activation of MKK7 by ASK1
        supporting_text: SKRP1 expression increased the ASK1-MKK7 complexes in a
          dose-dependent manner and specifically enhanced the activation of MKK7
          by ASK1
  - id: PMID:12050113
    title: ASK1 is essential for endoplasmic reticulum stress-induced neuronal 
      cell death triggered by expanded polyglutamine repeats.
    findings:
      - statement: ER stress activates ASK1 through IRE1-TRAF2-ASK1 complex 
          formation
        supporting_text: ER stress activates ASK 1 through formation of an 
          IRE1-TRAF2-ASK1 complex
      - statement: ASK1-/- neurons are defective in ER stress-induced JNK 
          activation and cell death
        supporting_text: ASK1(-/-) primary neurons are defective in polyQ-, 
          proteasome inhibitor-, and ER stress-induced JNK activation and cell 
          death
  - id: PMID:12556535
    title: Type 1 insulin-like growth factor receptor (IGF-IR) signaling 
      inhibits apoptosis signal-regulating kinase 1 (ASK1).
    findings: []
  - id: PMID:12813029
    title: AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating 
      dissociation of ASK1 from its inhibitor 14-3-3.
    findings: []
  - id: PMID:14557248
    title: Identification of a novel antiapoptotic protein that antagonizes ASK1
      and CAD activities.
    findings: []
  - id: PMID:14761963
    title: Positive regulation of apoptosis signal-regulating kinase 1 by 
      hD53L1.
    findings: []
  - id: PMID:15023544
    title: Interaction of apoptosis signal-regulating kinase 1 with isoforms of 
      14-3-3 proteins.
    findings: []
  - id: PMID:15246877
    title: S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide 
      system activates apoptosis signal-regulating kinase 1.
    findings: []
  - id: PMID:15983381
    title: Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating 
      kinase 1 activity and cell death.
    findings:
      - statement: DJ-1 protects against oxidative stress by sequestering Daxx
        supporting_text: wild-type DJ-1 sequesters Daxx in the nucleus, prevents
          it from gaining access to the cytoplasm
      - statement: Daxx activates ASK1 when in cytoplasm
        supporting_text: from binding to and activating its effector kinase 
          apoptosis signal-regulating kinase 1
      - statement: ASK1-/- primary neurons are defective in stress-induced cell 
          death
        supporting_text: the regulated sequestration of Daxx in the nucleus and 
          keeping apoptosis signal-regulating kinase 1 activation in check is a 
          critical mechanism by which DJ-1 exerts its cytoprotective function
  - id: PMID:16449798
    title: Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK 
      pathway activity in livers of aged and long-lived Snell dwarf mice.
    findings: []
  - id: PMID:16636664
    title: Human glutathione S-transferase P1-1 interacts with TRAF2 and 
      regulates TRAF2-ASK1 signals.
    findings: []
  - id: PMID:16648474
    title: Direct interaction and reciprocal regulation between ASK1 and 
      calcineurin-NFAT control cardiomyocyte death and growth.
    findings: []
  - id: PMID:17210579
    title: Apoptosis signal-regulating kinase (ASK) 2 functions as a 
      mitogen-activated protein kinase kinase kinase in a heteromeric complex 
      with ASK1.
    findings:
      - statement: ASK1 forms heteromeric complex with ASK2
        supporting_text: ASK2, a highly related serine/threonine kinase to ASK1,
          also functions as a MAP3K only in a heteromeric complex with ASK1
      - statement: ASK2 requires ASK1 for stability and MAP3K function
        supporting_text: endogenous ASK2 was constitutively degraded in 
          ASK1-deficient cells, suggesting that ASK1 is required for the 
          stability of ASK2
      - statement: ASK2 activates ASK1 by direct phosphorylation
        supporting_text: ASK2 was found to activate ASK1 by direct 
          phosphorylation
  - id: PMID:17389591
    title: RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is 
      critical for tumor necrosis factor-induced ASK1-JNK/p38 activation.
    findings: []
  - id: PMID:17700517
    title: G1 to S phase transition protein 1 induces apoptosis 
      signal-regulating kinase 1 activation by dissociating 14-3-3 from ASK1.
    findings: []
  - id: PMID:17761141
    title: Connexin 43 confers resistance to hydrogen peroxide-mediated 
      apoptosis.
    findings: []
  - id: PMID:17937911
    title: Structural and functional characterization of the human protein 
      kinase ASK1.
    findings:
      - statement: ASK1 catalytic domain forms tight dimer (Kd ~0.2 uM)
        supporting_text: Sedimentation velocity measurements led to the 
          determination of an apparent sedimentation coefficient corrected for 
          water at 20°C, s20,w0, of 4.518 S, as well as the determination of a 
          protein molecular weight of 66 kDa, which is in excellent agreement 
          with the expected mass of an ASK1 catalytic domain dimer
      - statement: Autophosphorylation at Thr813, Thr838, Thr842 regulates 
          signaling
        supporting_text: Reporter gene assays showed that all three identified 
          in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate 
          ASK1 signaling
      - statement: Crystal structure solved in complex with staurosporine
        supporting_text: Here, we present the structure of the human ASK1 
          catalytic domain in complex with staurosporine
  - id: PMID:19590015
    title: Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic 
      activity as a protein serine/threonine phosphatase to activate ASK1.
    findings: []
  - id: PMID:19782076
    title: A scanning peptide array approach uncovers association sites within 
      the JNK/beta arrestin signalling complex.
    findings: []
  - id: PMID:19805025
    title: CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced 
      signaling by targeting ASK1.
    findings: []
  - id: PMID:19935702
    title: Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to
      the ASK1 signalosome.
    findings: []
  - id: PMID:20674765
    title: Protein phosphatase with EF-hand domains 2 (PPEF2) is a potent 
      negative regulator of apoptosis signal regulating kinase-1 (ASK1).
    findings:
      - statement: PPEF2 interacts with and negatively regulates ASK1
        supporting_text: We identify human PPEF2 as a novel interacting partner 
          and a negative regulator of ASK1
      - statement: PPEF2 suppresses H2O2-induced ASK1 activation
        supporting_text: PPEF2 efficiently suppressed H(2)O(2)-induced 
          activation of ASK1
      - statement: ASK1 activation leads to caspase-3 cleavage
        supporting_text: prevented ASK1-dependent caspase-3 cleavage and 
          activation
  - id: PMID:21496457
    title: Stabilization of the survival motor neuron protein by ASK1.
    findings: []
  - id: PMID:21771788
    title: Positive regulation of apoptosis signal-regulating kinase 1 signaling
      by ZPR9 protein, a zinc finger protein.
    findings:
      - statement: ZPR9 is a positive regulator of ASK1
        supporting_text: ZPR9 was found to physically interact with apoptosis 
          signal-regulating kinase 1 (ASK1)
      - statement: ZPR9 stimulates ASK1-mediated JNK and p38 signaling
        supporting_text: Ectopic expression of wild-type ZPR9, but not an 
          S314A/T318A mutant, stimulated ASK1 kinase activity and positively 
          regulated ASK1-mediated signaling to both JNK and p38 kinases
      - statement: ZPR9 destabilizes ASK1-Trx and ASK1-14-3-3 complexes
        supporting_text: by destabilizing complex formation between ASK1 and its
          negative regulators, Trx and 14-3-3
  - id: PMID:22095282
    title: Arginine methylation-dependent regulation of ASK1 signaling by PRMT1.
    findings: []
  - id: PMID:22609355
    title: Microspherule protein 2 associates with ASK1 and acts as a negative 
      regulator of stress-induced ASK1 activation.
    findings: []
  - id: PMID:23000344
    title: Ursolic acid induces ER stress response to activate ASK1-JNK 
      signaling and induce apoptosis in human bladder cancer T24 cells.
    findings:
      - statement: ER stress induces IRE1-TRAF2-ASK1 complex formation
        supporting_text: Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex 
          formation to activate pro-apoptotic ASK1-JNK signaling
      - statement: ASK1-JNK signaling promotes apoptosis in response to ER 
          stress
        supporting_text: ursolic acid induces a significant ER stress response 
          in cultured human bladder cancer T24 cells
  - id: PMID:25241761
    title: Using an in situ proximity ligation assay to systematically profile 
      endogenous protein-protein interactions in a pathway network.
    findings: []
  - id: PMID:25852190
    title: Integrative analysis of kinase networks in TRAIL-induced apoptosis 
      provides a source of potential targets for combination therapy.
    findings: []
  - id: PMID:26095851
    title: Cyclophilin A regulates JNK/p38-MAPK signaling through its physical 
      interaction with ASK1.
    findings:
      - statement: CypA binds ASK1 and negatively regulates its function
        supporting_text: CypA regulates apoptosis signaling-regulating kinase 1 
          (ASK1) through its direct binding
      - statement: CypA negatively regulates ASK1 Ser966 phosphorylation
        supporting_text: CypA negatively regulates phosphorylation of ASK1 at 
          Ser966
      - statement: ASK1 induces caspase-3 activation and apoptosis
        supporting_text: ASK1 is known to induce caspase-3 activation and 
          apoptosis
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:31980649
    title: Extensive rewiring of the EGFR network in colorectal cancer cells 
      expressing transforming levels of KRAS(G13D).
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
    findings: []
  - id: PMID:9743501
    title: Activation of apoptosis signal-regulating kinase 1 (ASK1) by the 
      adapter protein Daxx.
    findings: []
  - id: Reactome:R-HSA-2559583
    title: Cellular Senescence
    findings: []
  - id: Reactome:R-HSA-3225851
    title: ROS oxidize thioredoxin and activate MAP3K5
    findings: []
  - id: Reactome:R-HSA-3228469
    title: MAP3K5 phosphorylates MKK3 and MKK6
    findings: []
  - id: Reactome:R-NUL-3299417
    title: MAP3K5 (ASK1) phosphorylates Map2k4(Sek1)
    findings: []
  - id: PMID:11003656
    title: Inhibition of Daxx-mediated apoptosis by heat shock protein 27.
    findings:
      - statement: HSP27 prevents interaction of Daxx with Ask1, blocking 
          Daxx-mediated apoptosis
        supporting_text: phosphorylated dimers of HSP27 interact with Daxx, a 
          mediator of Fas-induced apoptosis, preventing the interaction of Daxx 
          with both Ask1 and Fas and blocking Daxx-mediated apoptosis
  - id: file:human/MAP3K5/MAP3K5-deep-research-falcon.md
    title: Deep research on MAP3K5 function
    findings: []
core_functions:
  - molecular_function:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    description: ASK1 functions as a serine/threonine MAP3K (EC 2.7.11.25) that 
      directly phosphorylates and activates MAP2K4/MKK4, MAP2K7/MKK7 (JNK 
      pathway), MAP2K3/MKK3, and MAP2K6/MKK6 (p38 pathway).
  - molecular_function:
      id: GO:0004706
      label: JUN kinase kinase kinase activity
    description: ASK1 specifically activates the JNK pathway by phosphorylating 
      MKK4 and MKK7.

MAP3K5

Gene Description

Existing Annotations Review

Core Functions

ASK1 functions as a serine/threonine MAP3K (EC 2.7.11.25) that directly phosphorylates and activates MAP2K4/MKK4, MAP2K7/MKK7 (JNK pathway), MAP2K3/MKK3, and MAP2K6/MKK6 (p38 pathway).

ASK1 specifically activates the JNK pathway by phosphorylating MKK4 and MKK7.

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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