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.
| 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 studies (PMID:17937911, PMID:23776076) confirmed the kinase domain structure and activity; the latter resolved ASK1 kinase-domain structures (PDB 4BF2, 4BHN, 4BIB-4BIE) with ATP-competitive inhibitors bound in the ATP pocket. 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) PMID:23776076 ASK1 activates the JNK and p38 pathways, but not the ERK pathway, and has been shown to directly phosphorylate MKK3, 4, and 6 PMID:23776076 ASK1 is a polypeptide chain of ∼1000 residues consisting of a central serine/threonine kinase domain...the structure of the kinase domain of human ASK1 has previously been determined, using co-crystallisation techniques, in complex with Staurosporin |
| 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. The ASK1 kinase-domain crystal structures (PMID:23776076; PDB 4BF2, 4BHN, 4BIB-4BIE) resolve this central serine/threonine kinase domain with ATP-competitive inhibitors bound in the ATP pocket. Reason: Redundant with the more specific MAP kinase kinase kinase activity term. MAP3Ks are serine/threonine kinases by definition. Supporting Evidence: PMID:23776076 ASK1 is a polypeptide chain of ∼1000 residues consisting of a central serine/threonine kinase domain and N- and C-terminal coiled coil domains PMID:23776076 the structure of the kinase domain of human ASK1 has previously been determined, using co-crystallisation techniques, in complex with Staurosporin...All the chemotypes make well-defined interactions with the kinase hinge |
| 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. Multiple ASK1 kinase-domain crystal structures with ATP-competitive inhibitors bound in the ATP pocket (PMID:23776076; PDB 4BF2, 4BHN, 4BIB-4BIE) further resolve 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 PMID:23776076 the ASK1 ATP binding site is able to accommodate a range of chemical diversity and provide a platform for further structure based drug design PMID:23776076 All the chemotypes make well-defined interactions with the kinase hinge...the areas of the active site accessed differ substantially between chemotypes |
| 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 |
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