ALPK1 is a cytosolic alpha-family protein kinase that couples recognition of microbial nucleotide-heptoses to innate immune signaling. Its N-terminal ligand-binding domain recognizes ADP-heptose, activating the C-terminal kinase to phosphorylate TIFA, prominently at Thr9. Phosphorylated TIFA oligomerizes and recruits downstream ubiquitin-ligase and kinase machinery that activates NF-ΞΊB and inflammatory gene expression. ALPK1 also occurs at centrosomes, mitotic spindle poles and ciliary bases in tested human cells; patient-cell ciliation abnormalities are documented, while the local biochemical mechanism remains less resolved. Disease-associated variants can increase signaling and broaden responsiveness to endogenous nucleotide sugars, helping explain ROSAH syndrome and selected adnexal tumors.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000922 spindle pole | IDA PMID:30967659 ALPK1 missense pathogenic variant in five families leads to ... | KEEP AS NON CORE | Summary: ALPK1 is detected at mitotic spindle poles in human retinal pigment epithelial cells. Reason: PMID:30967659 Figure 4aβf shows endogenous ALPK1 immunostaining at spindle poles in ARPE19 cells, with tubulin costaining. This is a supported cell-cycle-associated pool; the study does not identify the local ALPK1 substrate or establish spindle assembly as its principal molecular role. Supporting Evidence: PMID:30967659 localization of ALPK1 in the spindle poles at metaphase |
| GO:0000922 spindle pole | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ALPK1 is detected at mitotic spindle poles in human retinal pigment epithelial cells. Reason: PMID:30967659 Figure 4aβf shows endogenous ALPK1 immunostaining at spindle poles in ARPE19 cells, with tubulin costaining. This is a supported cell-cycle-associated pool; the study does not identify the local ALPK1 substrate or establish spindle assembly as its principal molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0448 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. Supporting Evidence: PMID:30967659 localization of ALPK1 in the spindle poles at metaphase |
| GO:0002753 cytoplasmic pattern recognition receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: ALPK1 initiates cytosolic bacterial nucleotide-heptose sensing through TIFA. Reason: The seeded PAINT node represents inherited intracellular microbial sensing. Human ALPK1 directly recognizes ADP-heptose and phosphorylates TIFA; mouse Alpk1-dependent inflammation is complementary organismal evidence. Target self-evidence in the descendant list is legitimate experimental grounding. No target-specific loss of this pathway role is evident. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002928819 SUPPORTS TRANSFER This is the ancestral PAINT node supplied by the seed. Human target experiments support the inherited kinase/innate-sensing biology; target self-evidence is legitimate descendant support. The local family metadata identifies PTHR46747, but no cached PAINT tree/IBD file was available to independently reconstruct node placement. Supporting Evidence: PMID:28222186 TIFA oligomerization was restored by overexpressing a siRNA-resistant full length ALPK1 construct. PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0002753 cytoplasmic pattern recognition receptor signaling pathway | IDA PMID:28222186 ALPK1 controls TIFA/TRAF6-dependent innate immunity against ... | ACCEPT | Summary: ALPK1 initiates cytosolic bacterial nucleotide-heptose sensing through TIFA. Reason: The full human-cell study places ALPK1 upstream of TIFA oligomerization and TRAF6/NF-ΞΊB activation: siRNA-resistant full-length ALPK1 rescues the phenotype, whereas the kinase-domain deletion does not. The original HBP interpretation is refined by the later ADP-heptose chemistry; the positive signaling experiments remain valid. Supporting Evidence: PMID:28222186 TIFA oligomerization was restored by overexpressing a siRNA-resistant full length ALPK1 construct. PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0002753 cytoplasmic pattern recognition receptor signaling pathway | IDA PMID:28877472 ALPK1- and TIFA-Dependent Innate Immune Response Triggered b... | ACCEPT | Summary: ALPK1 initiates cytosolic bacterial nucleotide-heptose sensing through TIFA. Reason: The abstract reports ALPK1-dependent TIFA phosphorylation, TIFAsome formation and NF-ΞΊB activation during H. pylori infection. These positive experiments agree with the independently established ALPK1βTIFA pathway. The local source is abstract-only, so detailed construct and assay scope is not inferred; the later ADP-heptose identification refines the original HBP model. Supporting Evidence: PMID:28877472 NF-ΞΊB activation, TIFA phosphorylation, and TIFAsome formation depend on a functional ALPK1 kinase PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0002753 cytoplasmic pattern recognition receptor signaling pathway | IDA PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | ACCEPT | Summary: ALPK1 initiates cytosolic bacterial nucleotide-heptose sensing through TIFA. Reason: The 2018 study combines receptor loss/rescue, direct ADP-heptose binding and TIFA phosphorylation. ALPK1 performs both recognition and the initiating kinase step, establishing process participation beyond genetic necessity. Human-cell biochemical work is distinct from the mouse inflammatory experiments. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0002753 cytoplasmic pattern recognition receptor signaling pathway | TAS Reactome:R-HSA-9645460 | ACCEPT | Summary: ALPK1 initiates cytosolic bacterial nucleotide-heptose sensing through TIFA. Reason: The curated human pathway explicitly places ALPK1 at cytosolic ligand recognition and TIFA phosphorylation before TRAF6/TAK1/IKK activation. This is direct participation in the receptor-signaling pathway, not attribution of the downstream partnersβ ubiquitin-ligase or kinase reactions to ALPK1. Supporting Evidence: Reactome:R-HSA-9645460 This Reactome module describes ALPK1 as a cytosolic innate immune receptor for bacterial ADP-heptose. |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | ACCEPT | Summary: ALPK1 is an ADP-heptose-activated protein serine/threonine kinase. Reason: Direct TIFA phosphorylation and kinase-inactive rescue controls support the broad serine/threonine-kinase class. The source-resolved TIFA site is Thr9. GO:0004674 includes threonine-specific kinase synonyms and threonine-directed activities, supporting retention of this conventional broad classification while the separate serine-specific assertions remain unresolved. The EXP and IDA source assertions are preserved separately. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:37072480 Data confirmed that ALPK1 induced the phosphorylation of TIFA on T9 residues in response to the recognition of ADPH |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ALPK1 is an ADP-heptose-activated protein serine/threonine kinase. Reason: Direct TIFA phosphorylation and kinase-inactive rescue controls support the broad serine/threonine-kinase class. The source-resolved TIFA site is Thr9. GO:0004674 includes threonine-specific kinase synonyms and threonine-directed activities, supporting retention of this conventional broad classification while the separate serine-specific assertions remain unresolved. The PAINT inference is consistent with target experimental evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002928819 SUPPORTS TRANSFER This is the ancestral PAINT node supplied by the seed. Human target experiments support the inherited kinase/innate-sensing biology; target self-evidence is legitimate descendant support. The local family metadata identifies PTHR46747, but no cached PAINT tree/IBD file was available to independently reconstruct node placement. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:37072480 Data confirmed that ALPK1 induced the phosphorylation of TIFA on T9 residues in response to the recognition of ADPH |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | ACCEPT | Summary: ALPK1 is an ADP-heptose-activated protein serine/threonine kinase. Reason: Direct TIFA phosphorylation and kinase-inactive rescue controls support the broad serine/threonine-kinase class. The source-resolved TIFA site is Thr9. GO:0004674 includes threonine-specific kinase synonyms and threonine-directed activities, supporting retention of this conventional broad classification while the separate serine-specific assertions remain unresolved. The EXP and IDA source assertions are preserved separately. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:37072480 Data confirmed that ALPK1 induced the phosphorylation of TIFA on T9 residues in response to the recognition of ADPH |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ALPK1 is an ADP-heptose-activated protein serine/threonine kinase. Reason: Direct TIFA phosphorylation and kinase-inactive rescue controls support the broad serine/threonine-kinase class. The source-resolved TIFA site is Thr9. GO:0004674 includes threonine-specific kinase synonyms and threonine-directed activities, supporting retention of this conventional broad classification while the separate serine-specific assertions remain unresolved. The alpha-kinase domains and EC mapping agree with the demonstrated human enzyme activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR004166 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. InterPro:IPR043529 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. EC:2.7.11.1 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:37072480 Data confirmed that ALPK1 induced the phosphorylation of TIFA on T9 residues in response to the recognition of ADPH |
| GO:0005515 protein binding | IPI PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | REMOVE | Summary: The ALPK1βTIFA interaction is part of the established kinaseβsubstrate mechanism. Reason: The source supports an ADP-heptose-dependent ALPK1βTIFA association and phosphorylation. Generic protein binding adds no informative molecular function beyond the already present kinase annotations from this same study. Remove the generic assertion without denying the interaction or adding a duplicate kinase replacement. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. Reactome:R-HSA-9645524 ADP-heptose stimulated coimmunoprecipitation of TIFA with ALPK1 and TRAF6 |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | UNDECIDED | Summary: The specific ALPK1β14-3-3 epsilon assay remains unverified. Reason: The paper maps human 14-3-3 interactomes, and the seeded IPI row identifies P62258 as the partner. The local abstract and retrieved PubMed record do not expose the ALPK1-specific result or supplemental target assay. The generic-binding default does not justify inventing a client-regulatory function or rejecting an uninspected curated interaction; retain uncertainty pending the actual target evidence. Supporting Evidence: PMID:36931259 we map the interactomes of all human 14-3-3 paralogs |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding supports the ALPK1 kinase reaction. Reason: InterPro maps the alpha-kinase domain to ATP binding. Human ALPK1 uses ATP to phosphorylate substrate; this cofactor interaction is intrinsic to the core catalytic mechanism, rather than a separate signaling activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR004166 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. Supporting Evidence: file:human/ALPK1/ALPK1-uniprot.txt L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] |
| GO:0005813 centrosome | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: ALPK1 has a supported centrosomal pool. Reason: Human Protein Atlas HPA027435 immunofluorescence supports centrosomal localization in A-431, U-251MG and ASC52telo cells; lack of staining in other tested lines is recorded separately and is not universal exclusion. The independent ARPE19 study corroborates this specialized pool. Supporting Evidence: PMID:30967659 in centrosomes of cells during interphase |
| GO:0005813 centrosome | IDA PMID:30967659 ALPK1 missense pathogenic variant in five families leads to ... | KEEP AS NON CORE | Summary: ALPK1 has a supported centrosomal pool. Reason: The full primary Figure 4dβi shows ALPK1 colocalization with gamma-tubulin at centrosomes in human ARPE19 cells during mitosis and interphase. Retain this contextual compartment without inferring a centrosome-specific kinase substrate. Supporting Evidence: PMID:30967659 in centrosomes of cells during interphase |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ALPK1 has a supported centrosomal pool. Reason: The full primary Figure 4dβi shows ALPK1 colocalization with gamma-tubulin at centrosomes in human ARPE19 cells during mitosis and interphase. Retain this contextual compartment without inferring a centrosome-specific kinase substrate. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0048 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. Supporting Evidence: PMID:30967659 in centrosomes of cells during interphase |
| GO:0005829 cytosol | IDA PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | ACCEPT | Summary: Cytosol is the principal compartment of ALPK1 innate immune sensing. Reason: The receptor recognizes nucleotide-heptose in the cytosol and phosphorylates TIFA there. The 2018 localization experiment and independent ARPE19 diffuse cytosolic staining support this location alongside the separately documented centrosomal pool. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosol is the principal compartment of ALPK1 innate immune sensing. Reason: The receptor recognizes nucleotide-heptose in the cytosol and phosphorylates TIFA there. The 2018 localization experiment and independent ARPE19 diffuse cytosolic staining support this location alongside the separately documented centrosomal pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0091 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645394 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TRAF6 synthesis of free K63-linked ubiquitin chains. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645406 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TAB2/TAB3βTAK1 recruitment to the ubiquitin-bearing signaling assembly. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645414 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TRAF6 autoubiquitination. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645428 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes direct binding of ADP-heptose to ALPK1. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645442 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TAK1 autophosphorylation within the downstream signaling assembly. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645481 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TIFA oligomerization following Thr9 phosphorylation. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645501 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TRAF6 oligomerization downstream of TIFA. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645520 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TIFA-dependent recruitment of TRAF6. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645524 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes ADP-heptose-dependent association of ALPK1 and TIFA. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645535 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes ALPK1-catalyzed TIFA Thr9 phosphorylation. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758604 | ACCEPT | Summary: The curated signaling event places ALPK1 in its cytosolic pathway context. Reason: This human Reactome event describes TRAF6-dependent IKBKG ubiquitination. The GO assertion is cytosolic location, consistent with the ALPK1 receptor/kinase pool and source pathway model. It does not assign the eventβs partner chemistry to ALPK1; the direct ALPK1 reaction is ligand-triggered TIFA phosphorylation. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:30967659 shows a diffuse cytosolic pattern and enrichment of ALPK1 in centrosomes of the cells |
| GO:0005929 cilium | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ALPK1 is detected at the base of primary cilia. Reason: Human ARPE19 microscopy in PMID:30967659 Figure 4jβl localizes ALPK1 at the ciliary base after serum starvation. HPA also reports ciliary basal-body staining in ASC52telo cells. Retain the original source resolution; the mouse photoreceptor connecting-cilium result is not relabeled as a human retinal experiment. This specialized pool is distinct from the established cytosolic innate-receptor mechanism. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002928819 SUPPORTS TRANSFER This is the ancestral PAINT node supplied by the seed. Human target experiments support the inherited ciliary localization, retained as a contextual pool. Supporting Evidence: PMID:30967659 Super-resolution confocal imaging showed the presence of ALPK1 in the base of primary cilia |
| GO:0005929 cilium | IDA PMID:30967659 ALPK1 missense pathogenic variant in five families leads to ... | KEEP AS NON CORE | Summary: ALPK1 is detected at the base of primary cilia. Reason: Human ARPE19 microscopy in PMID:30967659 Figure 4jβl localizes ALPK1 at the ciliary base after serum starvation. HPA also reports ciliary basal-body staining in ASC52telo cells. Retain the original source resolution; the mouse photoreceptor connecting-cilium result is not relabeled as a human retinal experiment. This specialized pool is distinct from the established cytosolic innate-receptor mechanism. Supporting Evidence: PMID:30967659 Super-resolution confocal imaging showed the presence of ALPK1 in the base of primary cilia |
| GO:0005929 cilium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ALPK1 is detected at the base of primary cilia. Reason: Human ARPE19 microscopy in PMID:30967659 Figure 4jβl localizes ALPK1 at the ciliary base after serum starvation. HPA also reports ciliary basal-body staining in ASC52telo cells. Retain the original source resolution; the mouse photoreceptor connecting-cilium result is not relabeled as a human retinal experiment. This specialized pool is distinct from the established cytosolic innate-receptor mechanism. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0066 SUPPORTS TRANSFER The seeded mapping source is preserved. Its domain, location or enzyme-class assertion agrees with the target-level source evidence discussed in the reason. Supporting Evidence: PMID:30967659 Super-resolution confocal imaging showed the presence of ALPK1 in the base of primary cilia |
| GO:0036064 ciliary basal body | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: ALPK1 is detected at the base of primary cilia. Reason: Human ARPE19 microscopy in PMID:30967659 Figure 4jβl localizes ALPK1 at the ciliary base after serum starvation. HPA also reports ciliary basal-body staining in ASC52telo cells. Retain the original source resolution; the mouse photoreceptor connecting-cilium result is not relabeled as a human retinal experiment. This specialized pool is distinct from the established cytosolic innate-receptor mechanism. Supporting Evidence: PMID:30967659 Super-resolution confocal imaging showed the presence of ALPK1 in the base of primary cilia |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:28222186 ALPK1 controls TIFA/TRAF6-dependent innate immunity against ... | ACCEPT | Summary: ALPK1 positively regulates canonical NF-ΞΊB signaling through TIFA. Reason: ALPK1 kinase activity promotes TIFA phosphorylation/oligomerization and downstream TRAF6βTAK1βIKK signaling. The full human-cell experiments show ALPK1 depletion blocks infection-induced IΞΊBΞ± degradation and p65 nuclear translocation, with kinase-domain-dependent rescue of TIFA oligomers. This is pathway-specific activation, not a claim that ALPK1 directly phosphorylates IKK or is required for all TNF/IL-1 signaling. Supporting Evidence: PMID:28222186 TIFA oligomerization was restored by overexpressing a siRNA-resistant full length ALPK1 construct. PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:28877472 ALPK1- and TIFA-Dependent Innate Immune Response Triggered b... | ACCEPT | Summary: ALPK1 positively regulates canonical NF-ΞΊB signaling through TIFA. Reason: ALPK1 kinase activity promotes TIFA phosphorylation/oligomerization and downstream TRAF6βTAK1βIKK signaling. The sourceβs positive ALPK1-dependent TIFA and NF-ΞΊB findings agree with this established mechanism. This is pathway-specific activation, not a claim that ALPK1 directly phosphorylates IKK or is required for all TNF/IL-1 signaling. Supporting Evidence: PMID:28877472 NF-ΞΊB activation, TIFA phosphorylation, and TIFAsome formation depend on a functional ALPK1 kinase PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | ACCEPT | Summary: ALPK1 positively regulates canonical NF-ΞΊB signaling through TIFA. Reason: ALPK1 kinase activity promotes TIFA phosphorylation/oligomerization and downstream TRAF6βTAK1βIKK signaling. The sourceβs positive ALPK1-dependent TIFA and NF-ΞΊB findings agree with this established mechanism. This is pathway-specific activation, not a claim that ALPK1 directly phosphorylates IKK or is required for all TNF/IL-1 signaling. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Microbial nucleotide-heptose recognition is an innate immune function of ALPK1. Reason: Ligand recognition and direct phosphorylation of the signaling adaptor constitute actual work in the innate response. Retain this valid broader core process alongside the more specific receptor-signaling annotation. Human cellular experiments and mouse inflammatory phenotypes are distinguished; disease-associated activation does not replace the wild-type mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002928819 SUPPORTS TRANSFER This is the ancestral PAINT node supplied by the seed. Human target experiments support the inherited kinase/innate-sensing biology; target self-evidence is legitimate descendant support. The local family metadata identifies PTHR46747, but no cached PAINT tree/IBD file was available to independently reconstruct node placement. Supporting Evidence: PMID:28222186 TIFA oligomerization was restored by overexpressing a siRNA-resistant full length ALPK1 construct. PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0045087 innate immune response | IDA PMID:28222186 ALPK1 controls TIFA/TRAF6-dependent innate immunity against ... | ACCEPT | Summary: Microbial nucleotide-heptose recognition is an innate immune function of ALPK1. Reason: Ligand recognition and direct phosphorylation of the signaling adaptor constitute actual work in the innate response. Retain this valid broader core process alongside the more specific receptor-signaling annotation. Human cellular experiments and mouse inflammatory phenotypes are distinguished; disease-associated activation does not replace the wild-type mechanism. Supporting Evidence: PMID:28222186 TIFA oligomerization was restored by overexpressing a siRNA-resistant full length ALPK1 construct. PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0045087 innate immune response | IDA PMID:28877472 ALPK1- and TIFA-Dependent Innate Immune Response Triggered b... | ACCEPT | Summary: Microbial nucleotide-heptose recognition is an innate immune function of ALPK1. Reason: Ligand recognition and direct phosphorylation of the signaling adaptor constitute actual work in the innate response. Retain this valid broader core process alongside the more specific receptor-signaling annotation. Human cellular experiments and mouse inflammatory phenotypes are distinguished; disease-associated activation does not replace the wild-type mechanism. Supporting Evidence: PMID:28877472 NF-ΞΊB activation, TIFA phosphorylation, and TIFAsome formation depend on a functional ALPK1 kinase PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0045087 innate immune response | IDA PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | ACCEPT | Summary: Microbial nucleotide-heptose recognition is an innate immune function of ALPK1. Reason: Ligand recognition and direct phosphorylation of the signaling adaptor constitute actual work in the innate response. Retain this valid broader core process alongside the more specific receptor-signaling annotation. Human cellular experiments and mouse inflammatory phenotypes are distinguished; disease-associated activation does not replace the wild-type mechanism. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0048029 monosaccharide binding | IBA GO_REF:0000033 | MODIFY | Summary: ALPK1 recognizes microbial ADP-heptose and initiates innate immune signaling. Reason: The intact ADP-heptose ligand is a nucleotide-sugar derivative, and binding stimulates ALPK1-dependent TIFA phosphorylation and innate signaling. Human N-terminal structural/binding evidence and wild-type versus kinase-inactive cellular rescue support pattern recognition receptor activity (GO:0038187), whose definition covers recognition of a microbial pattern that initiates an innate response. This functional refinement is more informative than carbohydrate derivative binding, an ancestor of the already retained ATP-binding annotation. It does not assert free-heptose binding, transfer partner signaling chemistry to ALPK1, or require a transmembrane receptor. The original IBA/IPI evidence and source entities are preserved. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002928819 SUPPORTS TRANSFER This is the ancestral PAINT node supplied by the seed. Human target experiments support the inherited nucleotide-heptose sensing activity. The target-level functional refinement uses direct ligand recognition coupled to signaling; it does not allege lineage loss, wrong node placement or circular target self-evidence. Proposed replacements: pattern recognition receptor activity Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0048029 monosaccharide binding | IPI PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | MODIFY | Summary: ALPK1 recognizes microbial ADP-heptose and initiates innate immune signaling. Reason: The intact ADP-heptose ligand is a nucleotide-sugar derivative, and binding stimulates ALPK1-dependent TIFA phosphorylation and innate signaling. Human N-terminal structural/binding evidence and wild-type versus kinase-inactive cellular rescue support pattern recognition receptor activity (GO:0038187), whose definition covers recognition of a microbial pattern that initiates an innate response. This functional refinement is more informative than carbohydrate derivative binding, an ancestor of the already retained ATP-binding annotation. It does not assert free-heptose binding, transfer partner signaling chemistry to ALPK1, or require a transmembrane receptor. The original IBA/IPI evidence and source entities are preserved. Proposed replacements: pattern recognition receptor activity Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. |
| GO:0060271 cilium assembly | IMP PMID:30967659 ALPK1 missense pathogenic variant in five families leads to ... | UNDECIDED | Summary: A ROSAH-associated ALPK1 variant is associated with defective primary-cilium assembly. Reason: The full source measures reduced ciliation in fibroblasts from two p.Thr237Met patients against one unaffected control after serum starvation, with three replicate experiments. Endogenous human ALPK1 localizes to the ciliary base, but localization and the patient phenotype do not resolve whether normal ALPK1 performs cilium-assembly work or whether altered signaling by the gain-of-function variant disrupts ciliogenesis. The HeLa wild-type/mutant overexpression comparison measures multinucleation rather than cilium assembly; no wild-type loss/rescue ciliation assay was identified in the inspected source. Preserve the positive mutant phenotype and curated IMP assertion, with an unresolved judgment about normal process participation. A dedicated ciliary enzyme or mapped substrate is not required in principle for such participation. Supporting Evidence: PMID:30967659 Affected family member fibroblasts demonstrated defective ciliogenesis. PMID:30967659 Super-resolution confocal imaging showed the presence of ALPK1 in the base of primary cilia |
| GO:0106310 protein serine kinase activity | EXP PMID:27169898 ALPK1 phosphorylates myosin IIA modulating TNF-Ξ± trafficking... | UNDECIDED | Summary: The myosin-IIA phosphorylation assay does not resolve a serine acceptor. Reason: The full paper shows ATP- and ALPK1-dependent phosphorylation of phosphatase-treated, immunoprecipitated myosin IIA, with omission controls. Detection uses ProQ and pan-phospho-Ser/Thr rather than a mapped serine site. ALPK1 purified from human HEK293F also coeluted endogenous myosin, a limitation the authors acknowledge. This positive kinase evidence supports the broader existing activity, while the exact serine-specific source assertion remains unresolved; no claim is made that ALPK1 lacks serine kinase capacity. Supporting Evidence: PMID:27169898 The phosphorylation of myosin IIA was strongly seen after incubation with both ALPK1 and ATP on the Pro-Q staining assay |
| GO:0106310 protein serine kinase activity | EXP PMID:30111836 Alpha-kinase 1 is a cytosolic innate immune receptor for bac... | UNDECIDED | Summary: The inspected TIFA evidence establishes threonine phosphorylation, while the serine-specific assertion remains unresolved. Reason: The source abstract, original first-page preview and publisher Extended Data captions support ADP-heptose-dependent TIFA phosphorylation at Thr9. The complete original Methods and remaining main results were not recovered. The newer human-cell kinase study also identifies TIFA threonines, which is not proof that the original study never assayed a serine substrate. Retain uncertainty rather than reject the experimental curatorβs narrower assertion from partial access. Supporting Evidence: PMID:30111836 ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. PMID:37072480 Data confirmed that ALPK1 induced the phosphorylation of TIFA on T9 residues in response to the recognition of ADPH |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | UNDECIDED | Summary: The serine-specific Rhea mapping inherits an unresolved residue-class assertion. Reason: RHEA:17989 correctly denotes phosphorylation of a protein serine residue, and the mapping itself is preserved. Its UniProt evidence points to the same two studies reviewed here: one pan-Ser/Thr myosin assay and one incompletely accessible TIFA study whose inspected site is Thr9. Those establish broad kinase activity but do not independently resolve the serine subactivity in this audit. Propagation Review Root cause: UNRESOLVED Sources checked: RHEA:17989 UNRESOLVED The seeded mapping source is preserved. Rhea supplies the serine reaction; supporting residue-specific experiments remain unresolved, rather than the mapping being mechanically wrong. Supporting Evidence: file:human/ALPK1/ALPK1-uniprot.txt L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] |
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Download this section (compressed HTML)Q: Does normal ALPK1 participate in cilium assembly, or does altered signaling by ROSAH variants secondarily disrupt ciliogenesis, and which experiments distinguish these mechanisms?
Q: What site-resolved human experiment supports the seeded serine-specific kinase activity, separately from TIFA threonine phosphorylation and pan-Ser/Thr myosin assays?
Q: How does ALPK1 discriminate microbial nucleotide-heptoses from endogenous nucleotide sugars, and how do ROSAH variants alter this selectivity?
Q: Does ALPK1 binding to 14-3-3 epsilon regulate its localization, aggregation or kinase activity under physiological conditions?
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