Affinage

TTBK2

Tau-tubulin kinase 2 · UniProt Q6IQ55

Length
1244 aa
Mass
137.4 kDa
Annotated
2026-04-28
34 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TTBK2 is a serine-threonine kinase that functions as a master regulator of primary cilium assembly, maintenance, and ciliary signaling, with additional roles in microtubule dynamics, synaptic receptor trafficking, and tau phosphorylation. It is recruited to the distal appendages of the mother centriole by CEP164—via direct binding and phase-separation-driven condensation—where it phosphorylates CEP83 to enable ciliary vesicle docking, triggers CP110 removal, and recruits IFT-A, IFT-B, and dynein-2 complexes required for ciliogenesis; after assembly, it maintains cilium stability by regulating centriolar satellites, IFT protein pools, and axonemal microtubule modifications, with its steady-state levels controlled by HUWE1-mediated proteasomal degradation (PMID:25297623, PMID:31455668, PMID:36322399, PMID:40305080, PMID:38879724, PMID:40483689). Beyond cilia, TTBK2 tracks microtubule plus ends via EB1/3 and phosphorylates KIF2A to inhibit microtubule depolymerization, promoting cell migration, and it modulates GluK2 glutamate receptor surface abundance through RAB5-dependent endocytosis (PMID:26323690, PMID:27607061). Truncating mutations in TTBK2 cause spinocerebellar ataxia type 11 (SCA11) by acting as dominant negatives that suppress kinase activity, impair ciliogenesis, and disrupt Sonic Hedgehog signaling, with conditional loss of TTBK2 in adult mice recapitulating cerebellar Purkinje cell degeneration (PMID:18037885, PMID:30532139, PMID:31934864).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 High

    Identifying TTBK2 as the SCA11 disease gene established that this kinase is essential for cerebellar neuronal survival and linked it to tau pathology, but the cellular mechanism was unknown.

    Evidence Linkage analysis and mutation screening in SCA11 families with neuropathological examination of affected brain tissue

    PMID:18037885

    Open questions at the time
    • Whether disease arises from loss of kinase function, dominant-negative effects, or gain-of-function was unresolved
    • Substrates beyond tau were not identified
    • No cellular mechanism connecting TTBK2 loss to neurodegeneration was proposed
  2. 2011 High

    Biochemical characterization revealed TTBK2's unusual substrate preference for phosphotyrosine-primed sites and showed that SCA11 truncations suppress kinase activity while increasing protein expression, establishing the enzymological framework for interpreting disease mutations.

    Evidence In vitro kinase assay with oriented peptide library, mutagenesis of phosphate-priming groove, SCA11 knockin mouse showing embryonic lethality

    PMID:21548880

    Open questions at the time
    • Physiological substrates primed by phosphotyrosine were not identified
    • How SCA11 truncations cause disease at the cellular level remained unclear
  3. 2014 High

    Discovery that CEP164 recruits TTBK2 to mother centriole distal appendages via a proline-rich motif, and that this recruitment is essential for CP110 removal and ciliogenesis, reframed TTBK2 as a centriolar kinase controlling cilium initiation.

    Evidence Reciprocal co-immunoprecipitation, TTBK2 binding-motif mutagenesis, siRNA depletion/rescue, in vitro kinase assay for CEP164 and CEP97

    PMID:25297623

    Open questions at the time
    • The direct centriolar substrates of TTBK2 required for ciliogenesis were not mapped
    • Structural basis of the CEP164–TTBK2 interaction was not determined
  4. 2015 High

    Demonstration that TTBK2 tracks microtubule plus ends via EB1/3 and phosphorylates KIF2A at S135 to inhibit MT depolymerization established a cilia-independent function in cytoskeletal regulation and cell migration.

    Evidence Co-IP, in vitro kinase assay with phosphosite identification, non-phosphorylatable mutant rescue, live-cell MT imaging, migration assays

    PMID:26323690

    Open questions at the time
    • Whether the EB1-dependent function is separable from the CEP164-dependent ciliogenesis role in vivo was unclear
    • Upstream signals regulating TTBK2 plus-end tracking were not identified
  5. 2016 Medium

    Showing that TTBK2 kinase activity drives RAB5-dependent endocytosis of the GluK2 glutamate receptor extended its functional repertoire to synaptic receptor trafficking, suggesting a direct synaptic role.

    Evidence Xenopus oocyte expression with dual-electrode voltage clamp, confocal imaging, dominant-negative RAB5 rescue

    PMID:27607061

    Open questions at the time
    • The direct phosphorylation target mediating GluK2 endocytosis was not identified
    • Relevance in mammalian neurons was not demonstrated
    • Heterologous expression system limits physiological interpretation
  6. 2018 High

    Two studies clarified the disease mechanism: TTBK2 synergizes with tau to cause neurodegeneration in C. elegans, and SCA11 truncating mutations act as dominant negatives that disrupt ciliogenesis and SHH signaling in mice, establishing ciliary dysfunction as a core disease driver.

    Evidence Transgenic C. elegans co-expression with tau; mouse allelic series with quantitative cilia IF and SHH reporter assays

    PMID:29409526 PMID:30532139

    Open questions at the time
    • Relative contributions of tau toxicity versus ciliary defects to SCA11 pathogenesis were not dissected
    • Whether SCA11 truncation retains partial kinase activity in vivo was not resolved
  7. 2019 High

    Identification of CEP83 as a direct TTBK2 substrate at four phosphosites, required for ciliary vesicle docking and CP110 removal, provided the first detailed mechanism of how TTBK2 kinase activity initiates ciliogenesis at the distal appendage.

    Evidence STORM/STED superresolution microscopy, in vitro kinase assay with mass spectrometry phosphosite mapping, CEP83 phospho-mutant functional analysis

    PMID:31455668

    Open questions at the time
    • Whether additional substrates are required alongside phospho-CEP83 was unknown
    • How CEP83 phosphorylation connects to CP110 removal machinery was not defined
  8. 2020 High

    Conditional Ttbk2 knockout in adult mouse brain phenocopied by Ift88 conditional knockout demonstrated that TTBK2's essential role in maintaining primary cilia—not a cilia-independent function—drives Purkinje cell degeneration and motor deficits in SCA11.

    Evidence Adult conditional knockout mice, behavioral assays, cilia quantification, genetic comparison with Ift88 CKO

    PMID:31934864

    Open questions at the time
    • Whether restoring cilia can rescue established degeneration was not tested
    • Cell-type-specific vulnerability within the cerebellum was not fully dissected
  9. 2021 High

    Structural determination of the CEP164–TTBK2 complex revealed how ciliopathic CEP164 mutations disrupt TTBK2 recruitment, providing atomic-level understanding of the ciliogenesis-initiating interaction.

    Evidence X-ray crystallography/NMR, biochemical binding assays, functional complementation with ciliopathy mutants

    PMID:34499853

    Open questions at the time
    • Structure of full-length TTBK2 was not solved
    • How kinase activation relates to binding was not determined
  10. 2022 High

    Post-assembly cilium maintenance was shown to require TTBK2 for regulating centriolar satellites, IFT protein pools, and suppressing actin-dependent cilia disassembly, extending TTBK2's role beyond initiation to ongoing cilium stability.

    Evidence Tamoxifen-inducible Ttbk2 deletion in MEFs, time-course immunofluorescence, actin inhibitor rescue

    PMID:36322399

    Open questions at the time
    • Direct substrates mediating satellite regulation and actin suppression were not identified
    • Whether maintenance and assembly functions use identical phosphorylation events was unclear
  11. 2023 Medium

    Pharmacological inhibition of TTBK2 phenocopied genetic knockout in human iPSCs, validating kinase activity as druggable and confirming catalytic requirement for ciliogenesis in a human cellular context.

    Evidence Indolyl pyrimidinamine inhibitor treatment with iPSC cilia quantification, comparison to TTBK2 KO

    PMID:37059819

    Open questions at the time
    • Inhibitor selectivity among related kinases was not fully profiled
    • In vivo pharmacological validation was not performed
  12. 2024 High

    Identification of HUWE1 as the E3 ligase targeting TTBK2 for proteasomal degradation at the centrosome established how TTBK2 protein levels are regulated to control cilia disassembly, linking TTBK2 turnover to SHH-dependent cerebellar development.

    Evidence Co-IP, ubiquitination assays, HUWE1/TTBK2 knockdown in GNPs and medulloblastoma cells, in vivo cerebellar development analysis

    PMID:38879724

    Open questions at the time
    • Signals triggering HUWE1-mediated TTBK2 degradation were not defined
    • Whether HUWE1 regulation of TTBK2 is relevant outside of cerebellar development was not tested
  13. 2025 High

    Three 2025 studies refined the recruitment mechanism and expanded functional scope: CEP164 forms phase-separated condensates with TTBK2 required for efficient recruitment; TTBK2 kinase activity recruits IFT-A/B and dynein-2 complexes independently of CP110 removal; a kinase-domain missense variant dysregulates cytoskeletal and TGF-β phosphoproteome pathways; and TTBK2 is required for sperm axoneme integrity during spermiogenesis.

    Evidence In vitro phase separation reconstitution plus live-cell imaging; KO/chimeric reconstitution with IFT quantification; CRISPR knock-in phosphoproteomics; intratesticular siRNA with TEM ultrastructure

    PMID:40305080 PMID:40483689 PMID:40581359 PMID:41422144

    Open questions at the time
    • Whether phase separation is regulated by upstream signals is unknown
    • The full complement of TTBK2 substrates at distal appendages remains unmapped
    • Whether the TGF-β phosphoproteome changes are direct or indirect is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive substrate map for TTBK2 at the centriole, the structural basis for its activation upon CEP164 binding, and the relative contributions of ciliary versus non-ciliary (tau, cytoskeletal) functions to SCA11 pathogenesis remain unresolved.
  • Full-length TTBK2 structure and activation mechanism not determined
  • Systematic identification of all centriolar substrates not completed
  • Whether tau phosphorylation contributes to SCA11 independently of ciliary defects is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005815 microtubule organizing center 6 GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 6 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 1
Partners
CEP164CEP83CEP97CP110EB1EB3HUWE1KIF2A

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 TTBK2 mutations (frameshift/truncating) cause spinocerebellar ataxia type 11 (SCA11), with affected brain tissue showing cerebellar degeneration and tau deposition, implicating TTBK2 in the tau phosphorylation cascade and cerebellar neuronal survival. Human genetic linkage/mutation analysis, neuropathology Nature genetics High 18037885
2011 TTBK2 has an unusual substrate specificity with preference for a phosphotyrosine at the +2 position relative to the phosphorylation site; SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity, and cause enhanced nuclear localization; homozygous SCA11 knockin mutation causes embryonic lethality at E10. In vitro kinase assay with peptide library, mutagenesis of putative phosphate-priming groove, knockin mouse model, cell fractionation/immunofluorescence The Biochemical journal High 21548880
2014 TTBK2 is recruited to the mother centriole via binding to distal appendage protein CEP164 through a proline-rich motif (not via EB1/SxIP motifs); CEP164 binding is essential for TTBK2's function in CP110 removal and ciliogenesis initiation. TTBK2 can phosphorylate CEP164 and CEP97 and inhibits the CEP164–Dishevelled-3 interaction in a kinase-activity-dependent manner. Reciprocal co-immunoprecipitation, TTBK2 binding-motif mutagenesis, siRNA depletion/rescue, in vitro kinase assay Genes to cells High 25297623
2015 TTBK2 acts as a microtubule plus-end tracking protein (+TIP) by binding EB1/3, and phosphorylates the MT-depolymerizing kinesin KIF2A at S135 in an EB1/3-dependent manner, inactivating its depolymerizing activity and stabilizing MT plus ends to promote cell migration. Co-immunoprecipitation, in vitro kinase assay, siRNA depletion, non-phosphorylatable KIF2A mutant expression, live-cell imaging of MT dynamics, cell migration assays The Journal of cell biology High 26323690
2018 TTBK2 co-expressed with tau in C. elegans synergistically exacerbates behavioral abnormalities, aberrant neuronal architecture, and neuron loss compared to either alone, indicating TTBK2 kinase activity drives tau-dependent neurodegeneration. TTBK2 co-expression with TDP-43 did not exacerbate TDP-43 proteinopathy phenotypes. Transgenic C. elegans co-expression, behavioral assays, immunofluorescence for phospho-tau and phospho-TDP-43 Molecular neurodegeneration Medium 29409526
2018 SCA11-associated truncating mutations in TTBK2 act as dominant negative alleles; the truncated protein (TTBK2SCA11) interferes with full-length TTBK2 function in ciliogenesis, reduces cilia number, and disrupts ciliary trafficking of Smoothened (SMO) and Sonic Hedgehog (SHH) signaling components. Ttbk2 allelic series in mice, quantitative cilia immunofluorescence, SMO/SHH pathway reporter assays, conditional mouse genetics PLoS genetics High 30532139
2019 TTBK2 phosphorylates CEP83 at four sites after being recruited to distal appendages by CEP164; TTBK2-dependent CEP83 phosphorylation is required for early ciliogenesis steps including ciliary vesicle docking and CP110 removal. Superresolution microscopy revealed serum starvation causes TTBK2 redistribution from the periphery toward the root of distal appendages. Superresolution microscopy (STORM/STED), in vitro kinase assay, phosphosite mapping by mass spectrometry, CEP164-dependent TTBK2 recruitment assays, CEP83 phospho-mutant functional analysis The Journal of cell biology High 31455668
2020 Conditional knockout of Ttbk2 in adult mice causes loss of primary cilia throughout the brain, motor coordination deficits, and Purkinje cell degeneration recapitulating SCA11; conditional knockout of the ciliary trafficking gene Ift88 produces nearly identical phenotypes, indicating that disruption of ciliary signaling is a key driver. Conditional knockout mouse, behavioral assays, immunofluorescence, genetic epistasis (Ttbk2 vs Ift88 conditional KO comparison) eLife High 31934864
2021 Structural and biochemical analysis of the CEP164-TTBK2 complex revealed how CEP164 recruits TTBK2 to centrioles, how two ciliopathic mutations in CEP164 compromise this interaction, and how CEP164 binding coordinates with TTBK2 activities. X-ray crystallography/NMR structural analysis, biochemical binding assays, functional complementation with ciliopathy mutants Structure High 34499853
2022 TTBK2 maintains cilium stability after assembly by regulating centriolar satellite composition, maintaining basal body pools of intraflagellar transport (IFT) proteins, and suppressing actin-based cilia disassembly; loss of TTBK2 increases cilia break frequency and reduces axonemal microtubule modifications. Tamoxifen-inducible Ttbk2 deletion in MEFs, immunofluorescence time-course, actin inhibitor rescue experiments, quantitative microscopy of IFT and satellite proteins Molecular biology of the cell High 36322399
2023 TTBK2 inhibition by a small molecule (indolyl pyrimidinamine 10) significantly reduces primary cilia formation on human iPSCs, phenocopying TTBK2 knockout and confirming TTBK2 kinase activity is required for ciliogenesis. Chemical tool compound, iPSC cilia quantification, comparison to genetic TTBK2 KO Scientific reports Medium 37059819
2023 SCA11-associated TTBK2 truncating mutations contain a bona fide peroxisomal targeting signal type 1 (PTS1); their expression reduces peroxisome numbers, disrupts peroxisome fission, and impairs ciliary SMO trafficking upon SHH signaling, revealing a neomorphic function of mutant TTBK2 in peroxisome biology. Immunofluorescence peroxisome quantification, peroxisome fission pathway analysis, SMO ciliary trafficking assays in RPE1 cells expressing SCA11 variants bioRxivpreprint Medium 36778451
2024 HUWE1 is an E3 ubiquitin ligase that targets TTBK2 for proteasomal degradation at the centrosome, driving primary cilia disassembly; TTBK2 stabilizes cilia by inhibiting their disassembly, thereby promoting granule neuron progenitor (GNP) proliferation in response to SHH during cerebellar development. Co-immunoprecipitation, ubiquitination assays, HUWE1 KD/TTBK2 KD in GNPs and medulloblastoma cells, primary cilia dynamics assays, in vivo cerebellar development analysis Cell death and differentiation High 38879724
2016 TTBK2 wild-type (but not kinase-dead mutant) decreases GluK2 glutamate receptor abundance at the cell membrane via RAB5-dependent endocytosis, reducing GluK2 currents; truncated SCA11-associated TTBK2(450) lacks this activity, suggesting TTBK2 kinase activity modulates synaptic receptor trafficking. Xenopus oocyte expression, dual-electrode voltage clamp, confocal microscopy of EGFP-GluK2, dominant-negative RAB5 rescue Cellular physiology and biochemistry Medium 27607061
2025 CEP164 forms dynamic condensates with TTBK2 through phase separation driven by multivalent electrostatic interactions via CEP164's intrinsically disordered region; this phase separation is required for efficient TTBK2 recruitment to distal appendages and cilia formation. In vitro phase separation assays, live-cell condensate imaging, electrostatic interaction mutagenesis, TTBK2 recruitment quantification at distal appendages Cell reports Medium 40483689
2025 CEP164 homodimerization via its central coiled-coil region is necessary for its localization to the mother centriole and subsequent TTBK2 recruitment; TTBK2 kinase activity and its interaction with CEP164 are required for recruitment of IFT-A, IFT-B, and dynein-2 complexes and removal of CP110 from the mother centriole, though CP110 removal is not always coupled with IFT protein recruitment. CEP164-KO and TTBK2-KO cell lines, reconstitution with chimeric and truncation constructs, immunofluorescence quantification of IFT machinery recruitment Molecular biology of the cell High 40305080
2025 A missense variant in the TTBK2 kinase domain (L209F), introduced by CRISPR/Cas9 knock-in, reduces TTBK2 protein levels, impairs kinase activity toward TDP-43, alters cytoskeleton-related protein levels, and dysregulates phosphoproteome pathways including cytoskeletal organization and TGF-β signaling. CRISPR/Cas9 knock-in cell model, quantitative phosphoproteomics, in-cell kinase activity assay, Western blot Scientific reports High 41422144
2025 TTBK2 is expressed in mouse testis and co-localizes with α-tubulin in the manchette during spermiogenesis; TTBK2 knockdown by intratesticular injection increases sperm tail deformity, reduces sperm motility, and disorganizes axonemal microtubule structure, with downregulation of CEP164, CEP83, and IFT88 expression. Intratesticular siRNA injection, transmission electron microscopy, RT-qPCR, Western blot, immunofluorescence co-localization Molecular human reproduction Medium 40581359

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway. Journal of hematology & oncology 189 28219405
2007 Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nature genetics 142 18037885
2020 Circular RNA TTBK2 regulates cell proliferation, invasion and ferroptosis via miR-761/ITGB8 axis in glioma. European review for medical and pharmacological sciences 87 32196629
2018 Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. Molecular neurodegeneration 77 29409526
2019 Phosphorylation of CEP83 by TTBK2 is necessary for cilia initiation. The Journal of cell biology 67 31455668
2020 TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons. eLife 64 31934864
2014 Binding to Cep164, but not EB1, is essential for centriolar localization of TTBK2 and its function in ciliogenesis. Genes to cells : devoted to molecular & cellular mechanisms 55 25297623
2012 PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines. International journal of cancer 52 22020623
2015 TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation. The Journal of cell biology 47 26323690
2018 Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability. PLoS genetics 45 30532139
2011 TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development. The Biochemical journal 42 21548880
2010 Spinocerebellar ataxia type 11 (SCA11) is an uncommon cause of dominant ataxia among French and German kindreds. Journal of neurology, neurosurgery, and psychiatry 40 20667868
2015 TTBK2: a tau protein kinase beyond tau phosphorylation. BioMed research international 36 25950000
2021 Molecular mechanisms underlying the role of the centriolar CEP164-TTBK2 complex in ciliopathies. Structure (London, England : 1993) 20 34499853
2023 Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis. Scientific reports 16 37059819
2020 Knockdown of circ-TTBK2 Inhibits Glioma Progression by Regulating miR-1283 and CHD1. Cancer management and research 16 33116862
2019 Circular RNA TTBK2 promotes the development of human glioma cells via miR-520b/EZH2 axis. European review for medical and pharmacological sciences 16 31858557
2022 TTBK2 controls cilium stability by regulating distinct modules of centrosomal proteins. Molecular biology of the cell 14 36322399
2017 A Novel TTBK2 De Novo Mutation in a Danish Family with Early-Onset Spinocerebellar Ataxia. Cerebellum (London, England) 14 27165044
2017 Human TTBK1, TTBK2 and MARK1 kinase toxicity in Drosophila melanogaster is exacerbated by co-expression of human Tau. Biology open 14 28711868
2009 Missense exchanges in the TTBK2 gene mutated in SCA11. Journal of neurology 14 19533200
2012 TTBK2 kinase: linking primary cilia and cerebellar ataxias. Cell 13 23141531
2024 Regulation of primary cilia disassembly through HUWE1-mediated TTBK2 degradation plays a crucial role in cerebellar development and medulloblastoma growth. Cell death and differentiation 11 38879724
2016 Tau Tubulin Kinase TTBK2 Sensitivity of Glutamate Receptor GluK2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 6 27607061
2023 Spinocerebellar ataxia type 11 (SCA11): TTBK2 variants, functions and associated disease mechanisms. Cerebellum (London, England) 4 36892783
2025 Phase separation of TTBK2 and CEP164 is necessary for ciliogenesis. Cell reports 2 40483689
2023 TTBK2 mutations associated with spinocerebellar ataxia type 11 disrupt peroxisome dynamics and ciliary localization of SHH signaling proteins. bioRxiv : the preprint server for biology 2 36778451
2026 TTBK2-Driven Ciliogenesis Is Required for Intrinsic Neuronal Regeneration After Spinal Cord Injury. CNS neuroscience & therapeutics 1 41578860
2025 Coordinated roles of the CEP164 homodimer and TTBK2 are required for recruitment of the IFT machinery to the mother centriole for ciliogenesis. Molecular biology of the cell 1 40305080
2023 Spinocerebellar ataxia type 11 (SCA11): An update. The European journal of neuroscience 1 37329117
2023 A Novel TTBK2 Mutation in a Chinese Pedigree with Spinocerebellar Ataxia 11. Cerebellum (London, England) 1 37848700
2025 TTBK2 affects sperm quality by regulating the expression of centrosomal proteins and flagellar transporters during spermiogenesis in mice. Molecular human reproduction 0 40581359
2025 Missense variant in TTBK2 kinase domain causes loss of function and impaired protein phosphorylation. Scientific reports 0 41422144
2024 TTBK2 T3290C mutation in spinocerebellar ataxia 11 interferes with ciliogenesis. Translational neuroscience 0 39380965