IKKepsilon, also called Ik2 or dTBK1, is a serine/threonine protein kinase that regulates polarized cytoskeletal organization and recycling-endosome traffic. Its substrates include Spn-F, Nuclear fallout and DIAP1, linking phosphorylation to transport, cell elongation and nonapoptotic caspase regulation. Localized kinase activity contributes to bristle growth, oocyte polarity and dendrite pruning. In enterocytes it also supports cyclic-dinucleotide/STING-dependent antiviral immunity through induced gene expression.
Summary: ATP is the phosphate donor for this experimentally active protein kinase. ATP binding is more specific than generic nucleotide binding and is consistent with its conserved kinase domain and measured protein phosphorylation.
Reason: ATP is the phosphate donor for this experimentally active protein kinase. ATP binding is more specific than generic nucleotide binding and is consistent with its conserved kinase domain and measured protein phosphorylation.
IMP PMID:16887350 IKK epsilon regulates F actin assembly and interacts with Dr...
KEEP AS NON CORE
Summary: The kinase regulates polarized cellular elongation through cytoskeletal remodeling and endosomal traffic. Cell morphogenesis is a correct downstream process but is less informative than these mechanisms.
Reason: The kinase regulates polarized cellular elongation through cytoskeletal remodeling and endosomal traffic. Cell morphogenesis is a correct downstream process but is less informative than these mechanisms.
IMP PMID:19917727 Asymmetric microtubule function is an essential requirement ...
ACCEPT
Summary: Ik2 is required for the organization of bristle microtubules, and its interaction with Spn-F couples kinase activity to cytoskeletal patterning. Retain the experimental bundle-formation annotation supported by the target-specific mutant phenotype.
Reason: Ik2 is required for the organization of bristle microtubules, and its interaction with Spn-F couples kinase activity to cytoskeletal patterning. Retain the experimental bundle-formation annotation supported by the target-specific mutant phenotype.
Summary: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
Reason: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
c-di-GMP-induced expression of srg3 was dTBK1 dependent
GO:0004674 protein serine/threonine kinase activity
IBA GO_REF:0000033
ACCEPT
Summary: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
Reason: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
We show that DmIKKvarepsilon promotes degradation of DIAP1 through direct phosphorylation.
GO:0004674 protein serine/threonine kinase activity
IDA PMID:21316589 IKKΞ΅ regulates cell elongation through recycling endosome sh...
ACCEPT
Summary: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
Reason: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
We show that DmIKKvarepsilon promotes degradation of DIAP1 through direct phosphorylation.
GO:0004674 protein serine/threonine kinase activity
IEA GO_REF:0000120
ACCEPT
Summary: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
Reason: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
Summary: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
Reason: Direct studies establish phosphorylation of Spn-F, Nuclear fallout and DIAP1 by Drosophila Ik2/IKKepsilon. These substrate experiments support the serine/threonine kinase activity independently of family labels and electronic mappings.
IPI PMID:14605208 A protein interaction map of Drosophila melanogaster.
UNDECIDED
Summary: This high-throughput protein-interaction annotation does not identify a mechanistic binding function in the accessible abstract, and the target interaction table has not been verified. Preserve the experimental observation unresolved rather than infer substrate identity or a pathway from a generic protein-binding label.
Reason: This high-throughput protein-interaction annotation does not identify a mechanistic binding function in the accessible abstract, and the target interaction table has not been verified. Preserve the experimental observation unresolved rather than infer substrate identity or a pathway from a generic protein-binding label.
Summary: Interaction with DIAP1 is part of the substrate-regulatory relationship underlying phosphorylation-dependent IAP turnover. Generic protein binding is retained as noncore relative to the kinase activity and does not define a separate molecular function.
Reason: Interaction with DIAP1 is part of the substrate-regulatory relationship underlying phosphorylation-dependent IAP turnover. Generic protein binding is retained as noncore relative to the kinase activity and does not define a separate molecular function.
IPI PMID:18796167 The Drosophila IKK-related kinase (Ik2) and Spindle-F protei...
KEEP AS NON CORE
Summary: Ik2 forms a physiological complex with Spn-F and associated localization machinery. Direct binding and transport experiments support the interaction, while generic protein binding is noncore relative to catalytic substrate regulation.
Reason: Ik2 forms a physiological complex with Spn-F and associated localization machinery. Direct binding and transport experiments support the interaction, while generic protein binding is noncore relative to catalytic substrate regulation.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
IPI PMID:24019068 Drosophila oocyte polarity and cytoskeleton organization req...
KEEP AS NON CORE
Summary: Ik2 forms a physiological complex with Spn-F and associated localization machinery. Direct binding and transport experiments support the interaction, while generic protein binding is noncore relative to catalytic substrate regulation.
Reason: Ik2 forms a physiological complex with Spn-F and associated localization machinery. Direct binding and transport experiments support the interaction, while generic protein binding is noncore relative to catalytic substrate regulation.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
IPI PMID:26092846 A transport and retention mechanism for the sustained distal...
KEEP AS NON CORE
Summary: Ik2 forms a physiological complex with Spn-F and associated localization machinery. Direct binding and transport experiments support the interaction, while generic protein binding is noncore relative to catalytic substrate regulation.
Reason: Ik2 forms a physiological complex with Spn-F and associated localization machinery. Direct binding and transport experiments support the interaction, while generic protein binding is noncore relative to catalytic substrate regulation.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
IPI PMID:38944040 Next-generation Drosophila protein interactome map and its f...
UNDECIDED
Summary: This high-throughput protein-interaction annotation does not identify a mechanistic binding function in the accessible abstract, and the target interaction table has not been verified. Preserve the experimental observation unresolved rather than infer substrate identity or a pathway from a generic protein-binding label.
Reason: This high-throughput protein-interaction annotation does not identify a mechanistic binding function in the accessible abstract, and the target interaction table has not been verified. Preserve the experimental observation unresolved rather than infer substrate identity or a pathway from a generic protein-binding label.
Summary: The conserved protein-kinase domain and multiple direct phosphorylation assays support ATP binding as part of catalysis. No alternative nucleotide-specific chemistry is inferred.
Reason: The conserved protein-kinase domain and multiple direct phosphorylation assays support ATP binding as part of catalysis. No alternative nucleotide-specific chemistry is inferred.
Summary: Ik2 acts on cytoplasmic substrates and is localized to punctate structures, cortical regions and the growing bristle tip. These primary observations support cytoplasmic localization.
Reason: Ik2 acts on cytoplasmic substrates and is localized to punctate structures, cortical regions and the growing bristle tip. These primary observations support cytoplasmic localization.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
IDA PMID:21316589 IKKΞ΅ regulates cell elongation through recycling endosome sh...
ACCEPT
Summary: Ik2 acts on cytoplasmic substrates and is localized to punctate structures, cortical regions and the growing bristle tip. These primary observations support cytoplasmic localization.
Reason: Ik2 acts on cytoplasmic substrates and is localized to punctate structures, cortical regions and the growing bristle tip. These primary observations support cytoplasmic localization.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
Summary: Ik2 acts on cytoplasmic substrates and is localized to punctate structures, cortical regions and the growing bristle tip. These primary observations support cytoplasmic localization.
Reason: Ik2 acts on cytoplasmic substrates and is localized to punctate structures, cortical regions and the growing bristle tip. These primary observations support cytoplasmic localization.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
IMP PMID:16887350 IKK epsilon regulates F actin assembly and interacts with Dr...
ACCEPT
Summary: The kinase controls F-actin turnover and polarized cytoskeletal organization. Spn-F binding and phosphorylation, together with target mutant phenotypes, support this cytoskeletal regulatory mechanism.
Reason: The kinase controls F-actin turnover and polarized cytoskeletal organization. Spn-F binding and phosphorylation, together with target mutant phenotypes, support this cytoskeletal regulatory mechanism.
IMP PMID:24019068 Drosophila oocyte polarity and cytoskeleton organization req...
KEEP AS NON CORE
Summary: Ik2-dependent regulation of Spn-F/Javelin-like supports oocyte cytoskeleton polarity and oskar/gurken localization. Retain axis specification as a developmental consequence of the underlying transport/cytoskeletal mechanism.
Reason: Ik2-dependent regulation of Spn-F/Javelin-like supports oocyte cytoskeleton polarity and oskar/gurken localization. Retain axis specification as a developmental consequence of the underlying transport/cytoskeletal mechanism.
IMP PMID:19917727 Asymmetric microtubule function is an essential requirement ...
KEEP AS NON CORE
Summary: Bristle morphology depends on local kinase-controlled microtubule, actin and endosome organization. The tissue-level morphogenesis term is retained as noncore relative to those direct mechanisms.
Reason: Bristle morphology depends on local kinase-controlled microtubule, actin and endosome organization. The tissue-level morphogenesis term is retained as noncore relative to those direct mechanisms.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
IKKΙ regulates the localization of recycling endosome regulators Rab11 and Dynein and phosphorylates their adaptor molecule, Nuclear fallout (Nuf).
GO:0009967 positive regulation of signal transduction
IEA GO_REF:0000117
KEEP AS NON CORE
Summary: Cyclic-dinucleotide/STING experiments support kinase-dependent immune signal output and induced gene expression. Retain this broad umbrella process as noncore relative to the defined antiviral pathway, without using the ARBA assertion itself as validation.
Reason: Cyclic-dinucleotide/STING experiments support kinase-dependent immune signal output and induced gene expression. Retain this broad umbrella process as noncore relative to the defined antiviral pathway, without using the ARBA assertion itself as validation.
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
Summary: Cyclic-dinucleotide/STING experiments support kinase-dependent immune signal output and induced gene expression. Retain this broad umbrella process as noncore relative to the defined antiviral pathway, without using the ARBA assertion itself as validation.
Reason: Cyclic-dinucleotide/STING experiments support kinase-dependent immune signal output and induced gene expression. Retain this broad umbrella process as noncore relative to the defined antiviral pathway, without using the ARBA assertion itself as validation.
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
Summary: Ik2 is required for dendrite severing during metamorphic pruning, and premature kinase activation induces precocious severing. Neuron remodeling is retained as a context-specific consequence of cytoskeletal regulation.
Reason: Ik2 is required for dendrite severing during metamorphic pruning, and premature kinase activation induces precocious severing. Neuron remodeling is retained as a context-specific consequence of cytoskeletal regulation.
IPI PMID:25453831 Toward a comprehensive map of the effectors of rab GTPases.
KEEP AS NON CORE
Summary: The Rab-affinity study identifies Ik2 in the relevant Rab-interaction datasets and confirms the punctate Golgi distribution of the Ik2βSpn-F complex. Preserve small-GTPase binding as a supported trafficking interaction, noncore relative to kinase activity; co-purification does not by itself establish the precise direct binding interface.
Reason: The Rab-affinity study identifies Ik2 in the relevant Rab-interaction datasets and confirms the punctate Golgi distribution of the Ik2βSpn-F complex. Preserve small-GTPase binding as a supported trafficking interaction, noncore relative to kinase activity; co-purification does not by itself establish the precise direct binding interface.
IMP PMID:21316589 IKKΞ΅ regulates cell elongation through recycling endosome sh...
ACCEPT
Summary: Phosphorylation of the Rab11/dynein adaptor Nuf regulates recycling-endosome transport, providing a direct mechanistic role in endocytic recycling.
Reason: Phosphorylation of the Rab11/dynein adaptor Nuf regulates recycling-endosome transport, providing a direct mechanistic role in endocytic recycling.
IKKΙ regulates the localization of recycling endosome regulators Rab11 and Dynein and phosphorylates their adaptor molecule, Nuclear fallout (Nuf).
GO:0032481 positive regulation of type I interferon production
IBA GO_REF:0000033
REMOVE
Summary: Drosophila has STING-dependent antiviral immunity but lacks interferons. The specific mammalian type-I-interferon production process cannot be transferred to the fly kinase. Target-specific antiviral signaling remains valid and is captured by the separate innate-immunity annotations.
Reason: Drosophila has STING-dependent antiviral immunity but lacks interferons. The specific mammalian type-I-interferon production process cannot be transferred to the fly kinase. Target-specific antiviral signaling remains valid and is captured by the separate innate-immunity annotations.
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
GO:0035160 maintenance of epithelial integrity, open tracheal system
IMP PMID:16887350 IKK epsilon regulates F actin assembly and interacts with Dr...
KEEP AS NON CORE
Summary: The primary study demonstrates altered polarized morphology of tracheal terminal cells in kinase mutants. Retain epithelial integrity as a tissue-level consequence of cytoskeletal regulation rather than a separate core biochemical activity.
Reason: The primary study demonstrates altered polarized morphology of tracheal terminal cells in kinase mutants. Retain epithelial integrity as a tissue-level consequence of cytoskeletal regulation rather than a separate core biochemical activity.
tracheal terminal cells, bristles, and arista laterals, which require accurate F actin assembly for their polarized elongation, all exhibited aberrantly branched morphology.
GO:0043065 positive regulation of apoptotic process
Summary: The accessible abstract establishes phosphorylation-dependent DIAP1 degradation and explicitly emphasizes nonapoptotic caspase functions. That does not by itself demonstrate positive regulation of apoptosis, but the full original experiment has not been inspected and may include a relevant context. Retain the experimental annotation unresolved rather than infer cell death from any caspase activation.
Reason: The accessible abstract establishes phosphorylation-dependent DIAP1 degradation and explicitly emphasizes nonapoptotic caspase functions. That does not by itself demonstrate positive regulation of apoptosis, but the full original experiment has not been inspected and may include a relevant context. Retain the experimental annotation unresolved rather than infer cell death from any caspase activation.
IGI PMID:19822670 Temporal regulation of Drosophila IAP1 determines caspase fu...
MARK AS OVER ANNOTATED
Summary: The full primary study places the demonstrated Ik2-dependent DIAP1 degradation effect after the final SOP division, during shaft elongation. It explicitly reports that phase-I degradation during division was not disturbed by Ik2 downregulation and calls for further work on cell division. This annotation overstates the demonstrated temporal role; shaft morphogenesis and nonapoptotic caspase regulation are supported.
Reason: The full primary study places the demonstrated Ik2-dependent DIAP1 degradation effect after the final SOP division, during shaft elongation. It explicitly reports that phase-I degradation during division was not disturbed by Ik2 downregulation and calls for further work on cell division. This annotation overstates the demonstrated temporal role; shaft morphogenesis and nonapoptotic caspase regulation are supported.
however, its degradation pattern was not disturbed in phase I, suggesting that there may be one or more other regulators of DIAP1 turnover during SOP cell division.
GO:0045089 positive regulation of innate immune response
IEA GO_REF:0000117
ACCEPT
Summary: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
Reason: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
IDA PMID:21316589 IKKΞ΅ regulates cell elongation through recycling endosome sh...
ACCEPT
Summary: The kinase is specifically activated and retained at the distal tip of growing bristles through Spn-F/Javelin-like-dependent transport and retention.
Reason: The kinase is specifically activated and retained at the distal tip of growing bristles through Spn-F/Javelin-like-dependent transport and retention.
IKKΞ΅ distal tip localization is regulated by Spindle-F (Spn-F), which is stably retained at the distal tip and functions as an adaptor linking IKKΞ΅ to cytoplasmic dynein.
GO:0051493 regulation of cytoskeleton organization
IPI PMID:18796167 The Drosophila IKK-related kinase (Ik2) and Spindle-F protei...
ACCEPT
Summary: The kinase controls F-actin turnover and polarized cytoskeletal organization. Spn-F binding and phosphorylation, together with target mutant phenotypes, support this cytoskeletal regulatory mechanism.
Reason: The kinase controls F-actin turnover and polarized cytoskeletal organization. Spn-F binding and phosphorylation, together with target mutant phenotypes, support this cytoskeletal regulatory mechanism.
IMP PMID:21316589 IKKΞ΅ regulates cell elongation through recycling endosome sh...
ACCEPT
Summary: The kinase controls F-actin turnover and polarized cytoskeletal organization. Spn-F binding and phosphorylation, together with target mutant phenotypes, support this cytoskeletal regulatory mechanism.
Reason: The kinase controls F-actin turnover and polarized cytoskeletal organization. Spn-F binding and phosphorylation, together with target mutant phenotypes, support this cytoskeletal regulatory mechanism.
Summary: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
Reason: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
Summary: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
Reason: Target-specific depletion of dTBK1/Ik2 in enterocytes blocks cyclic-dinucleotide/STING-dependent antiviral protection and affects induced immune gene expression. This directly supports an innate antiviral signaling role in flies, without implying mammalian interferon production.
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
CDN-mediated protection from enteric SINV infection was lost in dSTING-enterocyte-depleted flies and in dTBK1-enterocyte-depleted flies compared to control flies
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Review rationale: Protein phosphorylation is directly established by experiments on fly Ik2 substrates Spn-F, Nuf and DIAP1. The selected Q9V3Y8 protein retains the complete kinase domain, and the broad reaction is already captured by experimentally supported serine/threonine kinase annotations. This is an equivalent known biological activity rather than a novel claim. It does not entail every mammalian TBK1 downstream pathway, particularly interferon production.
Supporting Evidence:
PMID:18796167: "We showed that Ik2 phosphorylates Spn-F and demonstrated that this phosphorylation does not lead to Spn-F degradation."
PMID:21316589: "IKKΙ regulates the localization of recycling endosome regulators Rab11 and Dynein and phosphorylates their adaptor molecule, Nuclear fallout (Nuf)."
PMID:16887178: "We show that DmIKKvarepsilon promotes degradation of DIAP1 through direct phosphorylation."