TTBK2 (tau tubulin kinase 2) is a casein kinase 1-family serine/threonine kinase with an N-terminal catalytic domain and a long C-terminal region that targets it to the mother centriole and to microtubule plus ends. It prefers substrates primed by a phosphotyrosine at the +2 position. At the onset of ciliogenesis, the distal appendage protein CEP164 binds TTBK2 and recruits it to the mother centriole, where TTBK2 phosphorylates distal appendage and cap regulators, including CEP83 and MPHOSPH9; MPHOSPH9 phosphorylation leads to its degradation and to removal of the ciliogenesis-suppressing CP110-CEP97 cap, after which IFT machinery is recruited and the axoneme grows. TTBK2 is essential for primary cilium formation in vivo and also supports cilium stability and ciliary trafficking after initiation. Through EB1/EB3 binding it also tracks microtubule plus ends and phosphorylates and inhibits KIF2A, stabilizing microtubules in migrating cells. Dominant truncating TTBK2 variants that inhibit its kinase activity cause spinocerebellar ataxia type 11.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000226 microtubule cytoskeleton organization | IGI PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: IGI with KIF2A: TTBK2 antagonizes KIF2A-dependent microtubule depolymerization. Reason: TTBK2 acts as an EB1/3-dependent microtubule plus-end tracking kinase that phosphorylates and inhibits KIF2A in migrating HeLa cells. This is supported experimentally but represents a secondary, non-ciliary function relative to its essential role in initiating ciliogenesis, so it is retained as non-core. Supporting Evidence: PMID:26323690 TTBK2 depletion reduced MT lifetime (facilitated shrinkage and suppressed rescue) and impaired HeLa cell migration, and these phenotypes were partially restored by KIF2A co-depletion. PMID:26323690 These findings indicate that TTBK2 with EB1/3 phosphorylates KIF2A and antagonizes KIF2A-induced depolymerization at MT plus ends for cell migration. |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA protein serine/threonine kinase activity across the CK1 family. Reason: TTBK2 is an active CK1-family Ser/Thr kinase; the IBA is consistent with direct biochemistry. Supporting Evidence: PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:21548880 TTBK2 kinase substrate specificity and the impact of spinoce... | ACCEPT | Summary: IDA: recombinant TTBK2 kinase activity and substrate specificity determined with peptide substrates. Reason: Direct biochemical evidence; core activity. Supporting Evidence: PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | ACCEPT | Summary: IDA: TTBK2 phosphorylates KIF2A at S135. Reason: Direct evidence of protein kinase activity on a protein substrate. Supporting Evidence: PMID:26323690 TTBK2 phosphorylated KIF2A at S135 in intact cells in an EB1/3-dependent fashion and inactivated its MT-depolymerizing activity in vitro. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from EC 2.7.11.1 / mouse orthologue. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:0004674 protein serine/threonine kinase activity | NAS PMID:28386764 Roles of tau protein in health and disease. | ACCEPT | Summary: NAS from a tau review listing TTBK1/2 among non-proline-directed Ser/Thr kinases. Reason: The statement is correct and corroborated by direct biochemistry, although the review is not primary evidence. Supporting Evidence: PMID:28386764 non-proline-directed serine/threonine-protein kinases, such as tau-tubulin kinase 1/2 (TTBK1/2) PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:0005515 protein binding | IPI PMID:22863007 Exome capture reveals ZNF423 and CEP164 mutations, linking r... | REMOVE | Summary: IPI with CEP164 (Q9UPV0). Reason: Bare protein binding is uninformative and no specific molecular function follows from this interaction alone; removal does not dispute the interaction. The CEP164 interaction is functionally central (it recruits TTBK2 to the mother centriole) and is represented on the CEP164 side as protein kinase binding. Supporting Evidence: PMID:24982133 These findings indicate that one of the major functions of Cep164 in ciliogenesis is to recruit active TTBK2 to centrioles. PMID:25297623 Using TTBK2 variants that contained mutations in the SxIP or proline-rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with KLHL12 (Q53G59) from a proteome-scale yeast two-hybrid map. Reason: Bare protein binding is uninformative and no specific molecular function follows from this interaction alone; removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | REMOVE | Summary: IPI with EB3/MAPRE3 (Q9UPY8): TTBK2 binds EB1/3 through SxIP motifs. Reason: Bare protein binding is uninformative and no specific molecular function follows from this interaction alone; removal does not dispute the interaction. The EB-dependent plus-end tracking is captured by the microtubule-related process rows. Supporting Evidence: PMID:26323690 We focused on tau-tubulin kinase 2 (TTBK2) as an EB1/3-binding kinase and confirmed that TTBK2 acted as a +TIP. |
| GO:0005515 protein binding | IPI PMID:27263857 MCRS1 associates with cytoplasmic dynein and mediates perice... | REMOVE | Summary: IPI with MCRS1 (Q96EZ8). Reason: Bare protein binding is uninformative and no specific molecular function follows from this interaction alone; removal does not dispute the interaction. MCRS1 association has been proposed to aid TTBK2 recruitment to the mother centriole. Supporting Evidence: PMID:27263857 Unlike NDE1, MCRS1 played a positive role for the initiation of ciliogenesis, possibly through its interaction with TTBK2. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with KLHL12 (Q53G59) from the HuRI binary interactome. Reason: Bare protein binding is uninformative and no specific molecular function follows from this interaction alone; removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with CEP164 (Q9UPV0) from a proteome-scale network. Reason: Bare protein binding is uninformative and no specific molecular function follows from this interaction alone; removal does not dispute the interaction. See the CEP164 review for the informative protein kinase binding annotation. Supporting Evidence: PMID:24982133 These findings indicate that one of the major functions of Cep164 in ciliogenesis is to recruit active TTBK2 to centrioles. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA ATP binding from the protein kinase domain signature. Reason: TTBK2 has an intact, active kinase domain; ATP binding is implied by its kinase activity. Supporting Evidence: PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:0005576 extracellular region | HDA PMID:22664934 Comparison of tear protein levels in breast cancer patients ... | MARK AS OVER ANNOTATED | Summary: HDA extracellular region from tear-fluid proteomics. Reason: TTBK2 is an intracellular kinase without a secretion signal; detection in tear fluid most likely reflects cell debris, and the cached text does not discuss TTBK2. Supporting Evidence: PMID:22664934 Over 150 proteins in the tear fluid of CTRL and CA were identified. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA nucleus across the CK1 family. Reason: TTBK2 is detected at low levels in the nucleus, increased for SCA11 truncation mutants. No nuclear function is known; retained as non-core. Supporting Evidence: PMID:21548880 We demonstrate that SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. |
| GO:0005634 nucleus | IDA PMID:21548880 TTBK2 kinase substrate specificity and the impact of spinoce... | KEEP AS NON CORE | Summary: IDA nucleus: low-level nuclear TTBK2, enhanced for SCA11 truncations. Reason: TTBK2 is detected at low levels in the nucleus, increased for SCA11 truncation mutants. No nuclear function is known; retained as non-core. Supporting Evidence: PMID:21548880 We demonstrate that SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA nucleus from UniProt subcellular location. Reason: TTBK2 is detected at low levels in the nucleus, increased for SCA11 truncation mutants. No nuclear function is known; retained as non-core. Supporting Evidence: PMID:21548880 We demonstrate that SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytoplasm. Reason: TTBK2 is cytoplasmic and acts at the mother centriole/basal body in the cytoplasm. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0005814 centriole | IDA PMID:23141541 The spinocerebellar ataxia-associated gene Tau tubulin kinas... | ACCEPT | Summary: IDA: TTBK2 localizes to the distal end of the mother centriole/basal body. Reason: Core location of TTBK2 function. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0005814 centriole | IEA GO_REF:0000120 | ACCEPT | Summary: IEA centriole from the mouse orthologue. Reason: Consistent with direct evidence. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence (GO_REF:0000052): cytosol (HPA main location). Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Supporting Evidence: PMID:24982133 These findings indicate that one of the major functions of Cep164 in ciliogenesis is to recruit active TTBK2 to centrioles. |
| GO:0005829 cytosol | IDA PMID:21548880 TTBK2 kinase substrate specificity and the impact of spinoce... | KEEP AS NON CORE | Summary: IDA cytosol from fractionation. Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Supporting Evidence: PMID:21548880 We demonstrate that SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA cytosol from UniProt subcellular location. Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Supporting Evidence: PMID:24982133 These findings indicate that one of the major functions of Cep164 in ciliogenesis is to recruit active TTBK2 to centrioles. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5617816 | KEEP AS NON CORE | Summary: Reactome TAS cytosol (RAB3IP/RAB8A reaction). Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Reactome models centrosomal reactions in the cytosol compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626227 | KEEP AS NON CORE | Summary: Reactome TAS cytosol (CP110/CEP97 dissociation). Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Reactome models centrosomal reactions in the cytosol compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626228 | KEEP AS NON CORE | Summary: Reactome TAS cytosol (distal appendage proteins recruit TTBK2). Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Reactome models centrosomal reactions in the cytosol compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626681 | KEEP AS NON CORE | Summary: Reactome TAS cytosol (recruitment of transition zone proteins). Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Reactome models centrosomal reactions in the cytosol compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626699 | KEEP AS NON CORE | Summary: Reactome TAS cytosol (MARK4 binds ODF2). Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Reactome models centrosomal reactions in the cytosol compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5638009 | KEEP AS NON CORE | Summary: Reactome TAS cytosol (CEP164 recruits RAB3IP vesicles). Reason: A diffuse cytosolic pool of TTBK2 exists (HPA main location; fractionation), from which TTBK2 is recruited to the mother centriole by CEP164. The functionally relevant location is the distal end of the mother centriole/basal body, so this is non-core. Reactome models centrosomal reactions in the cytosol compartment. |
| GO:0005929 cilium | IEA GO_REF:0000044 | ACCEPT | Summary: IEA cilium from UniProt subcellular location. Reason: TTBK2 localizes to the ciliary base/transition zone, which GO treats as part of the cilium; HPA also detects it in the primary cilium. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0007026 negative regulation of microtubule depolymerization | IDA PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: IDA: TTBK2 phosphorylates KIF2A and inactivates its depolymerizing activity, extending microtubule lifetime. Reason: TTBK2 acts as an EB1/3-dependent microtubule plus-end tracking kinase that phosphorylates and inhibits KIF2A in migrating HeLa cells. This is supported experimentally but represents a secondary, non-ciliary function relative to its essential role in initiating ciliogenesis, so it is retained as non-core. Supporting Evidence: PMID:26323690 TTBK2 phosphorylated KIF2A at S135 in intact cells in an EB1/3-dependent fashion and inactivated its MT-depolymerizing activity in vitro. PMID:26323690 TTBK2 depletion reduced MT lifetime (facilitated shrinkage and suppressed rescue) and impaired HeLa cell migration, and these phenotypes were partially restored by KIF2A co-depletion. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA signal transduction propagated across the CK1 family. Reason: Very general term placed at a deep CK1-family node. For TTBK2 the specific, supported roles are cilium assembly initiation and microtubule dynamics; no TTBK2-specific signal transduction role is established beyond its requirement for cilia-dependent signaling. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000225966 SUPPORTS SOURCE BUT NOT TARGET Deep CK1-family node; signal transduction is a generic family-level process that does not describe the specific centriolar and microtubule roles of TTBK2. Supporting Evidence: PMID:23141541 Here, we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. |
| GO:0007224 smoothened signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA smoothened signaling pathway from mouse Ttbk2. Reason: Loss of Shh signaling in Ttbk2 mutants is a consequence of the absence of cilia; TTBK2 also affects ciliary SMO trafficking after initiation. TTBK2 is required for, but not a demonstrated component of, the pathway. Supporting Evidence: PMID:23141541 We identified a null allele of mouse Ttbk2 based on loss of Sonic hedgehog activity, a signaling pathway that requires the primary cilium. Despite a normal basal body template, Ttbk2 mutants lack cilia. PMID:30532139 Our studies have also revealed new functions for TTBK2 after cilia initiation in the control of cilia length, trafficking of a subset of SHH pathway components, including Smoothened (SMO), and cilia stability. |
| GO:0007224 smoothened signaling pathway | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS smoothened signaling pathway from mouse Ttbk2. Reason: As for the IEA row: an indirect consequence of the cilium assembly defect. Supporting Evidence: PMID:23141541 We identified a null allele of mouse Ttbk2 based on loss of Sonic hedgehog activity, a signaling pathway that requires the primary cilium. Despite a normal basal body template, Ttbk2 mutants lack cilia. |
| GO:0015630 microtubule cytoskeleton | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA (ARBA) microtubule cytoskeleton. Reason: TTBK2 tracks growing microtubule plus ends via EB1/3; plausible but secondary to its centriolar location. Supporting Evidence: PMID:26323690 We focused on tau-tubulin kinase 2 (TTBK2) as an EB1/3-binding kinase and confirmed that TTBK2 acted as a +TIP. |
| GO:0018105 peptidyl-serine phosphorylation | IDA PMID:21548880 TTBK2 kinase substrate specificity and the impact of spinoce... | ACCEPT | Summary: IDA peptidyl-serine phosphorylation (peptide substrate characterization). Reason: Direct evidence that TTBK2 phosphorylates serine residues. Supporting Evidence: PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:0018105 peptidyl-serine phosphorylation | IDA PMID:30375385 M-Phase Phosphoprotein 9 regulates ciliogenesis by modulatin... | ACCEPT | Summary: IDA: TTBK2 phosphorylates MPHOSPH9 at the onset of ciliogenesis. Reason: Direct evidence of TTBK2-dependent phosphorylation of a ciliogenesis substrate. Supporting Evidence: PMID:30375385 After phosphorylation by Tau Tubulin Kinase 2 (TTBK2) at the beginning of ciliogenesis, MPP9 is targeted for degradation via the ubiquitin-proteasome system, which facilitates the removal of CP110 and CEP97 from the distal end of the mother centriole. |
| GO:0019894 kinesin binding | IPI PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: IPI with mouse KIF2A (Q9WV63). Reason: KIF2A is a TTBK2 substrate; the binding is a kinase-substrate interaction in the microtubule-dynamics function, which is non-core. Supporting Evidence: PMID:26323690 TTBK2 phosphorylated KIF2A at S135 in intact cells in an EB1/3-dependent fashion and inactivated its MT-depolymerizing activity in vitro. |
| GO:0021549 cerebellum development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA cerebellum development from mouse. Reason: Mouse cerebellar granule neuron migration was impaired by Ttbk2 knockdown, and TTBK2 truncations cause SCA11. This is a downstream developmental consequence of TTBK2 functions (microtubule dynamics and cilia) rather than a core activity; retained as non-core. Supporting Evidence: PMID:26323690 Collectively, our results indicate that TTBK2 is generally required for cell migration and that the functional depletion of TTBK2 impairs cerebellar development by affecting cell migration. |
| GO:0021549 cerebellum development | ISS PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: ISS cerebellum development from mouse. Reason: Mouse cerebellar granule neuron migration was impaired by Ttbk2 knockdown, and TTBK2 truncations cause SCA11. This is a downstream developmental consequence of TTBK2 functions (microtubule dynamics and cilia) rather than a core activity; retained as non-core. Supporting Evidence: PMID:26323690 Collectively, our results indicate that TTBK2 is generally required for cell migration and that the functional depletion of TTBK2 impairs cerebellar development by affecting cell migration. |
| GO:0021681 cerebellar granular layer development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA cerebellar granular layer development from mouse. Reason: Mouse cerebellar granule neuron migration was impaired by Ttbk2 knockdown, and TTBK2 truncations cause SCA11. This is a downstream developmental consequence of TTBK2 functions (microtubule dynamics and cilia) rather than a core activity; retained as non-core. Supporting Evidence: PMID:26323690 Collectively, our results indicate that TTBK2 is generally required for cell migration and that the functional depletion of TTBK2 impairs cerebellar development by affecting cell migration. |
| GO:0021681 cerebellar granular layer development | ISS PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: ISS cerebellar granular layer development from mouse. Reason: Mouse cerebellar granule neuron migration was impaired by Ttbk2 knockdown, and TTBK2 truncations cause SCA11. This is a downstream developmental consequence of TTBK2 functions (microtubule dynamics and cilia) rather than a core activity; retained as non-core. Supporting Evidence: PMID:26323690 Collectively, our results indicate that TTBK2 is generally required for cell migration and that the functional depletion of TTBK2 impairs cerebellar development by affecting cell migration. |
| GO:0021935 cerebellar granule cell precursor tangential migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA cerebellar granule cell precursor tangential migration from mouse. Reason: Mouse cerebellar granule neuron migration was impaired by Ttbk2 knockdown, and TTBK2 truncations cause SCA11. This is a downstream developmental consequence of TTBK2 functions (microtubule dynamics and cilia) rather than a core activity; retained as non-core. Supporting Evidence: PMID:26323690 Collectively, our results indicate that TTBK2 is generally required for cell migration and that the functional depletion of TTBK2 impairs cerebellar development by affecting cell migration. |
| GO:0021935 cerebellar granule cell precursor tangential migration | ISS PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: ISS cerebellar granule cell precursor tangential migration from mouse. Reason: Mouse cerebellar granule neuron migration was impaired by Ttbk2 knockdown, and TTBK2 truncations cause SCA11. This is a downstream developmental consequence of TTBK2 functions (microtubule dynamics and cilia) rather than a core activity; retained as non-core. Supporting Evidence: PMID:26323690 Collectively, our results indicate that TTBK2 is generally required for cell migration and that the functional depletion of TTBK2 impairs cerebellar development by affecting cell migration. |
| GO:0030334 regulation of cell migration | IGI PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: IGI with KIF2A: TTBK2 depletion impairs HeLa cell migration, rescued partly by KIF2A co-depletion. Reason: TTBK2 acts as an EB1/3-dependent microtubule plus-end tracking kinase that phosphorylates and inhibits KIF2A in migrating HeLa cells. This is supported experimentally but represents a secondary, non-ciliary function relative to its essential role in initiating ciliogenesis, so it is retained as non-core. Supporting Evidence: PMID:26323690 TTBK2 depletion reduced MT lifetime (facilitated shrinkage and suppressed rescue) and impaired HeLa cell migration, and these phenotypes were partially restored by KIF2A co-depletion. |
| GO:0035869 ciliary transition zone | IBA GO_REF:0000033 | ACCEPT | Summary: IBA ciliary transition zone; TTBK2 among the sources. Reason: TTBK2 acts at the distal end of the basal body/ciliary base; HPA also detects it at the primary cilium transition zone. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0035869 ciliary transition zone | IDA PMID:23141541 The spinocerebellar ataxia-associated gene Tau tubulin kinas... | ACCEPT | Summary: IDA transition zone (Goetz et al.). Reason: Direct localization at the distal basal body. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0035869 ciliary transition zone | IEA GO_REF:0000107 | ACCEPT | Summary: IEA transition zone from mouse. Reason: Consistent with direct evidence. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0035869 ciliary transition zone | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transition zone from mouse. Reason: Consistent with direct evidence. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0036064 ciliary basal body | IBA GO_REF:0000033 | ACCEPT | Summary: IBA ciliary basal body. Reason: TTBK2 is recruited by CEP164 to the distal appendages of the mother centriole/basal body. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. PMID:24982133 These findings indicate that one of the major functions of Cep164 in ciliogenesis is to recruit active TTBK2 to centrioles. |
| GO:0036064 ciliary basal body | IEA GO_REF:0000107 | ACCEPT | Summary: IEA ciliary basal body from mouse. Reason: Consistent. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0036064 ciliary basal body | ISS GO_REF:0000024 | ACCEPT | Summary: ISS ciliary basal body from mouse. Reason: Consistent. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0048156 tau protein binding | NAS PMID:28386764 Roles of tau protein in health and disease. | MARK AS OVER ANNOTATED | Summary: NAS tau protein binding from a tau review. Reason: Inferred from TTBK1/2 being listed as tau kinases; transient kinase-substrate contact is captured by the kinase activity terms and a physiological TTBK2-tau interaction has not been established. Supporting Evidence: PMID:28386764 non-proline-directed serine/threonine-protein kinases, such as tau-tubulin kinase 1/2 (TTBK1/2) PMID:21548880 Whether endogenous TTBK1 and/or TTBK2 regulate phosphorylation of endogenous tau has not been established. |
| GO:0050321 tau-protein kinase activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA (ARBA) tau-protein kinase activity. Reason: A TTBK2 catalytic fragment purified from brain phosphorylates tau in vitro and the kinase is named for this activity, but whether TTBK2 phosphorylates tau physiologically has not been established. Retained as a non-core, in vitro activity. Supporting Evidence: PMID:21548880 Whether endogenous TTBK1 and/or TTBK2 regulate phosphorylation of endogenous tau has not been established. file:human/TTBK2/TTBK2-deep-research-falcon.md phosphorylation is driven principally by TTBK1, not TTBK2 |
| GO:0050321 tau-protein kinase activity | NAS PMID:28386764 Roles of tau protein in health and disease. | KEEP AS NON CORE | Summary: NAS tau-protein kinase activity from a tau review. Reason: A TTBK2 catalytic fragment purified from brain phosphorylates tau in vitro and the kinase is named for this activity, but whether TTBK2 phosphorylates tau physiologically has not been established. Retained as a non-core, in vitro activity. Supporting Evidence: PMID:28386764 non-proline-directed serine/threonine-protein kinases, such as tau-tubulin kinase 1/2 (TTBK1/2) |
| GO:0050321 tau-protein kinase activity | TAS PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: TAS tau-protein kinase activity (Watanabe et al.). Reason: A TTBK2 catalytic fragment purified from brain phosphorylates tau in vitro and the kinase is named for this activity, but whether TTBK2 phosphorylates tau physiologically has not been established. Retained as a non-core, in vitro activity. Supporting Evidence: PMID:21548880 Whether endogenous TTBK1 and/or TTBK2 regulate phosphorylation of endogenous tau has not been established. |
| GO:0051010 microtubule plus-end binding | TAS PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | MARK AS OVER ANNOTATED | Summary: TAS microtubule plus-end binding: TTBK2 is an EB1/3-binding +TIP. Reason: TTBK2 accumulates at growing plus ends by binding EB1/EB3 through SxIP motifs, i.e. indirectly; direct microtubule plus-end binding has not been shown. Supporting Evidence: PMID:26323690 We focused on tau-tubulin kinase 2 (TTBK2) as an EB1/3-binding kinase and confirmed that TTBK2 acted as a +TIP. |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cilium assembly; TTBK2 among the sources. Reason: TTBK2 is a dedicated, essential regulator of ciliogenesis initiation. Supporting Evidence: PMID:23141541 Here, we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. |
| GO:0060271 cilium assembly | IEA GO_REF:0000107 | ACCEPT | Summary: IEA cilium assembly from mouse. Reason: Consistent. Supporting Evidence: PMID:23141541 Here, we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. |
| GO:0060271 cilium assembly | IMP PMID:23141541 The spinocerebellar ataxia-associated gene Tau tubulin kinas... | ACCEPT | Summary: IMP: Ttbk2 null mice lack cilia; TTBK2 is required to remove CP110 and recruit IFT. Reason: TTBK2 catalyses phosphorylation of ciliogenesis substrates (CEP83, MPHOSPH9, CEP164) at the mother centriole, i.e. it performs steps of cilium initiation. Supporting Evidence: PMID:23141541 Here, we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. PMID:31455668 TTBK2-dependent CEP83 phosphorylation is important for early ciliogenesis steps, including ciliary vesicle docking and CP110 removal. PMID:30375385 After phosphorylation by Tau Tubulin Kinase 2 (TTBK2) at the beginning of ciliogenesis, MPP9 is targeted for degradation via the ubiquitin-proteasome system, which facilitates the removal of CP110 and CEP97 from the distal end of the mother centriole. |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: ISS cilium assembly from mouse. Reason: Consistent. Supporting Evidence: PMID:23141541 Here, we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. |
| GO:0097546 ciliary base | IEA GO_REF:0000107 | ACCEPT | Summary: IEA ciliary base from mouse. Reason: TTBK2 is at the ciliary base. Supporting Evidence: PMID:23141541 TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. |
| GO:0106310 protein serine kinase activity | EXP PMID:21548880 TTBK2 kinase substrate specificity and the impact of spinoce... | ACCEPT | Summary: EXP protein serine kinase activity (RHEA reaction, peptide substrates). Reason: Direct biochemical evidence. Supporting Evidence: PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IEA protein serine kinase activity from RHEA mapping. Reason: Consistent. Supporting Evidence: PMID:21548880 In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. |
| GO:1902817 negative regulation of protein localization to microtubule | IMP PMID:26323690 TTBK2 with EB1/3 regulates microtubule dynamics in migrating... | KEEP AS NON CORE | Summary: IMP negative regulation of protein localization to microtubule (KIF2A at plus ends). Reason: TTBK2 acts as an EB1/3-dependent microtubule plus-end tracking kinase that phosphorylates and inhibits KIF2A in migrating HeLa cells. This is supported experimentally but represents a secondary, non-ciliary function relative to its essential role in initiating ciliogenesis, so it is retained as non-core. Supporting Evidence: PMID:26323690 These findings indicate that TTBK2 with EB1/3 phosphorylates KIF2A and antagonizes KIF2A-induced depolymerization at MT plus ends for cell migration. |
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Download this section (compressed HTML)Q: Which TTBK2 phosphorylation events (on CEP83, MPHOSPH9, CEP164, CEP97 or others) are individually necessary and sufficient for CP110-CEP97 cap removal?
Q: Does TTBK2 phosphorylate tau or other neuronal substrates physiologically, and does this contribute to SCA11 independently of cilia?
Experiment: Use analog-sensitive TTBK2 knock-in cells with thiophosphate labelling to map direct substrates at the mother centriole during serum starvation, then test phospho-null substrate mutants for CP110 removal and ciliogenesis.
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