SEK-1 is a dual-specificity mitogen-activated protein kinase kinase (MAPKK) that functions as a central component of the conserved p38 MAPK signaling cascade (nsy-1 -> sek-1 -> pmk-1). This kinase phosphorylates and activates PMK-1 (the C. elegans p38 MAPK ortholog) on both serine/threonine and tyrosine residues. SEK-1 plays essential roles in two major biological processes: (1) innate immune responses against bacterial and fungal pathogens, where it activates PMK-1-dependent transcription of antimicrobial peptides and stress response genes; and (2) asymmetric neuronal cell fate determination in the AWC olfactory neurons, where it acts downstream of calcium/CaMKII signaling to repress str-2 expression. SEK-1 is also involved in oxidative stress responses via PMK-1-mediated nuclear localization of SKN-1 and stabilization of RNT-1. The protein is activated by NSY-1 (MAPKKK)-mediated phosphorylation at Ser-204 and Thr-208.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: SEK-1 is definitively part of the p38 MAPK cascade, functioning between NSY-1 (MAPKKK) and PMK-1 (p38 MAPK). This has been demonstrated in multiple studies showing the signaling hierarchy (PMID:11751572, PMID:12142542). The phylogenetic inference from PAINT is consistent with experimental data. Reason: Core function well-established by multiple experimental studies. SEK-1 is the direct MAPKK in the conserved p38 cascade. Supporting Evidence: PMID:12142542 RNA interference assays and biochemical analysis established that a p38 ortholog, pmk-1, functions as the downstream MAP kinase required for pathogen defense PMID:11751572 the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII file:worm/sek-1/sek-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0004708 MAP kinase kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: SEK-1 has demonstrated MAP kinase kinase activity, phosphorylating PMK-1/p38 on both serine/threonine and tyrosine residues (PMID:11751572). The IBA annotation accurately reflects this core molecular function. Reason: Core molecular function supported by direct biochemical evidence. SEK-1 phosphorylates and activates PMK-1 (p38 MAPK). Supporting Evidence: PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric development |
| GO:0000165 MAPK cascade | IEA GO_REF:0000117 | ACCEPT | Summary: This IEA annotation from ARBA machine learning correctly identifies SEK-1's role in the MAPK cascade. It is consistent with the more specific IBA annotation and extensive experimental evidence. Reason: Accurate automated annotation consistent with experimental evidence. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: As a kinase, SEK-1 requires nucleotide binding for catalytic activity. However, this is a very general term; ATP binding (GO:0005524) would be more informative. Reason: Accurate but very general annotation for a kinase. The more specific ATP binding annotation is also present. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: SEK-1 has protein kinase activity as demonstrated by its ability to phosphorylate PMK-1. However, this is a broad term; more specific terms like MAP kinase kinase activity are more informative. Reason: Accurate parent term for the more specific MAP kinase kinase activity. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000043 | ACCEPT | Summary: SEK-1 phosphorylates PMK-1 on serine and threonine residues as part of its dual-specificity kinase activity. This annotation is accurate. Reason: Component of the dual-specificity kinase activity demonstrated for SEK-1. |
| GO:0004708 MAP kinase kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC-based annotation correctly identifies SEK-1's MAP kinase kinase activity (EC 2.7.12.2). This is consistent with experimental evidence. Reason: Accurate annotation based on enzyme classification, supported by experimental data. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: SEK-1 is a dual-specificity kinase that phosphorylates tyrosine in addition to serine/threonine. This annotation is accurate for a MAPKK. Reason: Component of dual-specificity kinase activity characteristic of MAPKKs. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: Kinases require ATP as a phosphate donor. The UniProt record indicates ATP binding at residues 56-64 and K79. Reason: Essential for kinase activity; supported by sequence analysis. |
| GO:0007399 nervous system development | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: SEK-1 is involved in AWC neuronal asymmetric development (PMID:11751572). This general term is accurate but non-specific. Reason: While accurate, the more specific term 'determination of left/right asymmetry in nervous system' (GO:0035545) better captures SEK-1's role. |
| GO:0016301 kinase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Very broad parent term; more specific kinase activity terms are present. Reason: Accurate parent term in the kinase hierarchy. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Very broad parent term for kinase activity. Reason: Accurate but very general parent term. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: Kinases typically require Mg2+ as a cofactor for ATP hydrolysis. This is a standard requirement for protein kinases. Reason: Accurate; metal ion binding (Mg2+) is required as cofactor for kinase activity. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: SEK-1 phosphorylates serine residues on its substrates. This is part of its dual-specificity kinase function. Reason: Component of dual-specificity kinase activity. |
| GO:0000165 MAPK cascade | IGI PMID:22308034 Stabilization of RNT-1 protein, runt-related transcription f... | ACCEPT | Summary: This study demonstrates SEK-1's role in the MAPK cascade in the context of oxidative stress response and RNT-1 stabilization. The IGI evidence with PMK-1 (Q17446) is appropriate. Reason: Well-supported by genetic interaction data in oxidative stress context. Supporting Evidence: PMID:22308034 The MAP kinase pathway is required for RNT-1 stabilization, and RNT-1 was phosphorylated by SEK-1/PMK-1 in vitro |
| GO:0000165 MAPK cascade | IMP PMID:20008556 The Caenorhabditis elegans Ste20-related kinase and Rac-type... | ACCEPT | Summary: This study examined MAPK pathways in stress response. While the paper primarily focuses on the JNK pathway (MLK-1-MEK-1-KGB-1), it provides context for MAPK signaling that includes the p38 pathway. Reason: IMP evidence for MAPK cascade involvement, though the paper emphasizes JNK pathway. Supporting Evidence: PMID:20008556 Dec 14. The Caenorhabditis elegans Ste20-related kinase and Rac-type small GTPase regulate the c-Jun N-terminal kinase signaling pathway mediating the stress response. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:17888400 Caenorhabditis elegans pgp-5 is involved in resistance to ba... | KEEP AS NON CORE | Summary: This study shows that SEK-1 is required for pgp-5 transcriptional induction in response to bacterial infection, which requires TIR-1 and the p38 MAPK cascade. Reason: This is a downstream consequence of SEK-1's role in the p38 cascade rather than a core function. The transcriptional activation is mediated by downstream transcription factors like SKN-1. Supporting Evidence: PMID:17888400 pgp-5 is induced by both bacterial infection and heavy metal stress |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:17888400 Caenorhabditis elegans pgp-5 is involved in resistance to ba... | ACCEPT | Summary: SEK-1 is required for resistance to Pseudomonas aeruginosa infection. The p38 MAPK pathway (including SEK-1) mediates innate immune responses against Gram-negative bacteria. Reason: Core function of SEK-1 in innate immunity is well-established. Multiple studies confirm this role (PMID:12142542, PMID:17888400, PMID:19454349). Supporting Evidence: PMID:12142542 A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance: sek-1 PMID:17888400 signals from both biotic and abiotic stresses are integrated by TIR-1... and a p38 MAP kinase signaling cassette |
| GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | IMP PMID:21857923 Dysregulated LRRK2 signaling in response to endoplasmic reti... | KEEP AS NON CORE | Summary: This study demonstrates that SEK-1/PMK-1 signaling protects against ER stress and dopaminergic neuron degeneration in the context of LRRK2 signaling. The sek-1 mutant shows enhanced sensitivity to 6-OHDA-induced neurotoxicity. Reason: This represents a specific context (dopaminergic neuron protection, LRRK2 pathway) rather than a core function of SEK-1. The term is quite specific to this study. Supporting Evidence: PMID:21857923 nematodes with a loss-of-function mutation in sek-1 consistently displayed enhanced susceptibility to 6-OHDA-induced neurotoxicity |
| GO:0004712 protein serine/threonine/tyrosine kinase activity | IDA PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | ACCEPT | Summary: This is direct biochemical evidence for SEK-1's dual-specificity kinase activity. The paper demonstrates that SEK-1 phosphorylates PMK-1 on both Ser/Thr and Tyr residues. Reason: Core molecular function with direct experimental evidence. This accurately describes SEK-1 as a dual-specificity MAPKK. Supporting Evidence: PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric development |
| GO:0006979 response to oxidative stress | IMP PMID:22308034 Stabilization of RNT-1 protein, runt-related transcription f... | ACCEPT | Summary: SEK-1 is required for stabilization of RNT-1 during oxidative stress and for the oxidative stress response mediated through PMK-1 and SKN-1. Reason: Important function of the p38 cascade in C. elegans oxidative stress response. Supporting Evidence: PMID:22308034 RNT-1 was rapidly stabilized by oxidative stress... The MAP kinase pathway is required for RNT-1 stabilization PMID:16166371 The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response |
| GO:0106310 protein serine kinase activity | IGI PMID:22308034 Stabilization of RNT-1 protein, runt-related transcription f... | ACCEPT | Summary: Genetic interaction with PMK-1 supports SEK-1's serine kinase activity in the context of RNT-1 phosphorylation during oxidative stress. Reason: Supports the biochemical evidence for SEK-1 kinase activity. Supporting Evidence: PMID:22308034 RNT-1 was phosphorylated by SEK-1/PMK-1 in vitro |
| GO:0140367 antibacterial innate immune response | IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans... | ACCEPT | Summary: This seminal paper established SEK-1's role in innate immunity against bacterial pathogens. sek-1 mutants show enhanced susceptibility to killing by P. aeruginosa and other pathogens. Reason: Core function of SEK-1 in innate immunity, established in the foundational paper for this pathway. Supporting Evidence: PMID:12142542 A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance: sek-1 |
| GO:0010628 positive regulation of gene expression | IMP PMID:22470487 The pseudokinase NIPI-4 is a novel regulator of antimicrobia... | KEEP AS NON CORE | Summary: SEK-1 is required for induction of antimicrobial peptide gene expression (nlp-29 cluster) following fungal infection. This is a downstream effect of the p38 cascade. Reason: This is a downstream consequence of SEK-1's signaling role rather than a core function. The annotation to immune response is more informative. Supporting Evidence: PMID:22470487 inductive signaling passes via TPA-1... and a MAPK cassette comprising the MAP3K NSY-1, the MAP2K SEK-1, and PMK-1 |
| GO:0050832 defense response to fungus | IMP PMID:22470487 The pseudokinase NIPI-4 is a novel regulator of antimicrobia... | ACCEPT | Summary: SEK-1 is required for antimicrobial peptide gene induction following infection with the fungus Drechmeria coniospora. This expands the innate immune function beyond bacteria. Reason: Important extension of SEK-1's innate immune function to fungal pathogens. Supporting Evidence: PMID:22470487 inductive signaling passes via TPA-1... and a MAPK cassette comprising the MAP3K NSY-1, the MAP2K SEK-1, and PMK-1... We have shown that for nlp-29 cluster genes, following both infection and injury |
| GO:0004708 MAP kinase kinase activity | IDA PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | ACCEPT | Summary: Direct biochemical demonstration of SEK-1's MAPKK activity, showing it phosphorylates and activates PMK-1. Reason: Core molecular function with direct experimental evidence. Supporting Evidence: PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric development |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: This study on mitochondrial UPR shows that pre-activation of UPR enhances survival of sek-1 mutants exposed to P. aeruginosa, confirming SEK-1's role in defense against Gram-negative bacteria. Reason: Additional evidence supporting SEK-1's role in defense against Gram-negative pathogens. Supporting Evidence: PMID:25274306 pre-activation of the UPRmt enhanced the survival of the pmk-1 and sek-1 mutants |
| GO:0050829 defense response to Gram-negative bacterium | IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: Genetic interaction with ATFS-1 in the context of P. aeruginosa defense supports SEK-1's role in innate immunity. Reason: Genetic interaction data supporting SEK-1's immune function. Supporting Evidence: PMID:25274306 pre-activation of the UPRmt enhanced the survival of the pmk-1 and sek-1 mutants |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:24972867 Orthosiphon stamineus protects Caenorhabditis elegans agains... | ACCEPT | Summary: This study shows SEK-1 is required for protection against Staphylococcus aureus infection. The p38 MAP kinase pathway mediates the protective effect. Reason: Extends SEK-1's innate immune function to Gram-positive pathogens. Supporting Evidence: PMID:24972867 The effect of UE-12 is diminished in sek-1 (km4) and pmk-1 (km25) mutants... the p38 MAP kinase and insulin-like signaling pathways |
| GO:0009636 response to toxic substance | IMP PMID:21408619 Global functional analyses of cellular responses to pore-for... | KEEP AS NON CORE | Summary: This study on cellular responses to pore-forming toxins shows that the p38 MAPK pathway (including SEK-1) is important for defense against bacterial toxins. Reason: Related to innate immunity function but very general. More specific defense response annotations are present. Supporting Evidence: PMID:21408619 the p38 mitogen-activated protein kinase (MAPK) pathway was the first intracellular pathway demonstrated to protect cells against PFTs |
| GO:0093002 response to nematicide | IMP PMID:15256590 Mitogen-activated protein kinase pathways defend against bac... | ACCEPT | Summary: SEK-1 is required for defense against bacterial pore-forming toxins like Cry5B from Bacillus thuringiensis. sek-1 is transcriptionally upregulated by Cry5B and mutants are hypersensitive to the toxin. Reason: Important function in response to natural nematode pathogens/toxins. Supporting Evidence: PMID:15256590 A p38 mitogen-activated protein kinase (MAPK) kinase and a c-Jun N-terminal-like MAPK are both transcriptionally up-regulated by Cry5B |
| GO:0000165 MAPK cascade | IGI PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | ACCEPT | Summary: Genetic interactions with nsy-1 (MAPKKK) and pmk-1 (MAPK) establish SEK-1's position in the MAPK cascade. Reason: Foundational genetic evidence for SEK-1's role in the p38 cascade. Supporting Evidence: PMID:11751572 the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII |
| GO:0031435 mitogen-activated protein kinase kinase kinase binding | IPI PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | ACCEPT | Summary: SEK-1 physically interacts with NSY-1 (MAPKKK). This interaction is essential for pathway function. Reason: Direct protein interaction evidence for SEK-1-NSY-1 binding. Supporting Evidence: PMID:11751572 SEK-1 functions in a pathway downstream of UNC-43 and NSY-1 |
| GO:0034607 turning behavior involved in mating | IMP PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | KEEP AS NON CORE | Summary: sek-1 mutants show defects in male mating behavior, likely related to neuronal signaling functions. Reason: This is likely a pleiotropic effect of the neuronal asymmetry function rather than a core function. Supporting Evidence: PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric development in Caenorhabditis elegans. |
| GO:0035545 determination of left/right asymmetry in nervous system | IMP PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | ACCEPT | Summary: SEK-1 is essential for establishing asymmetric cell fates in the AWC olfactory neurons. This is one of the two major biological roles of SEK-1. Reason: Core function of SEK-1 in neuronal development, established in the foundational paper. Supporting Evidence: PMID:11751572 SEK-1 is required for asymmetric expression in AWC neurons... the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII and establishes asymmetric cell fate decision during neuronal development |
| GO:0035545 determination of left/right asymmetry in nervous system | IGI PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | ACCEPT | Summary: Genetic interaction with nsy-1 in the context of AWC asymmetry supports this annotation. Reason: Genetic evidence supporting the neuronal asymmetry function. Supporting Evidence: PMID:11751572 Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1 |
| GO:0046662 regulation of egg-laying behavior | IMP PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as... | KEEP AS NON CORE | Summary: sek-1 mutants show egg-laying defects. The UniProt record notes "Egg-laying defect" for the G212R mutant. Reason: This is likely a pleiotropic effect rather than a core function. Supporting Evidence: PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric development in Caenorhabditis elegans. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans... | ACCEPT | Summary: The foundational paper showed sek-1 mutants have enhanced susceptibility to Enterococcus faecalis (Gram-positive). Reason: Core innate immunity function established in the foundational paper. Supporting Evidence: PMID:12142542 A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance: sek-1 |
| GO:0038066 p38MAPK cascade | IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans... | ACCEPT | Summary: This is the most specific term for SEK-1's role in the MAPK cascade. The paper establishes SEK-1 as a component of the conserved p38 MAPK pathway. Reason: Most appropriate specific term for SEK-1's signaling function. Supporting Evidence: PMID:12142542 RNA interference assays and biochemical analysis established that a p38 ortholog, pmk-1, functions as the downstream MAP kinase |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans... | ACCEPT | Summary: sek-1 was identified in a screen for mutants with enhanced susceptibility to P. aeruginosa (Gram-negative). Reason: Core innate immunity function from the foundational study. Supporting Evidence: PMID:12142542 A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance: sek-1 |
| GO:1901046 positive regulation of egg-laying behavior | IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans... | KEEP AS NON CORE | Summary: sek-1 mutants show reduced egg-laying. This annotation is more specific than 'regulation of egg-laying behavior'. Reason: Pleiotropic effect; not a core function of SEK-1. Supporting Evidence: PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. |
| GO:0000302 response to reactive oxygen species | IMP PMID:16166371 The C. elegans p38 MAPK pathway regulates nuclear localizati... | ACCEPT | Summary: SEK-1/PMK-1 pathway regulates SKN-1 nuclear localization during oxidative stress. gcs-1 expression in response to arsenite requires this pathway. Reason: Important stress response function linked to core p38 signaling. Supporting Evidence: PMID:16166371 The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response |
| GO:0000303 response to superoxide | IMP PMID:16166371 The C. elegans p38 MAPK pathway regulates nuclear localizati... | ACCEPT | Summary: More specific child term of response to ROS. The p38 pathway responds to oxidative stress including superoxide. Reason: Specific oxidative stress response function. Supporting Evidence: PMID:16166371 In response to oxidative stress, PMK-1 phosphorylates SKN-1 |
| GO:0045087 innate immune response | IMP PMID:19454349 Conditioning protects C. elegans from lethal effects of ente... | ACCEPT | Summary: SEK-1 is required for conditioning-mediated protection against enteropathogenic E. coli. The p38 MAPK pathway mediates this innate immune response. Reason: Core innate immunity function. Supporting Evidence: PMID:19454349 Conditioning requires dopaminergic neurons; the p38 MAP kinase pathway, which regulates innate immunity |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:19454349 Conditioning protects C. elegans from lethal effects of ente... | ACCEPT | Summary: Protection against enteropathogenic E. coli requires SEK-1/PMK-1 signaling. Reason: Additional evidence for innate immune function against Gram-negative bacteria. Supporting Evidence: PMID:19454349 Conditioning requires... the p38 MAP kinase pathway, which regulates innate immunity |
| GO:0045087 innate immune response | IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans... | ACCEPT | Summary: Foundational evidence for SEK-1's role in innate immunity. sek-1 mutants show enhanced susceptibility to multiple pathogens. Reason: Core function established in the seminal paper. Supporting Evidence: PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity |
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