| 2007 |
Mutations in TTBK2 (truncating) cause spinocerebellar ataxia type 11 (SCA11), with affected brain tissue showing cerebellar degeneration and tau deposition, establishing TTBK2 as a tau kinase important in the tau cascade and cerebellar degeneration. |
Genetic linkage and mutation analysis in human pedigrees; neuropathological examination of affected brain tissue |
Nature genetics |
High |
18037885
|
| 2011 |
TTBK2 has an unusual substrate specificity with preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity, and lead to enhanced nuclear localization. Homozygous SCA11 knock-in mutation causes embryonic lethality at ~E10. |
In vitro kinase assays with peptide substrates (TTBKtide), kinase domain modeling and mutagenesis, knockin mouse model, immunofluorescence for localization |
The Biochemical journal |
High |
21548880
|
| 2014 |
TTBK2 binds CEP164 through a proline-rich motif and EB1 through SxIP motifs, but binding to CEP164 (not EB1) is essential for centriolar localization of TTBK2. CEP164-dependent TTBK2 localization is required for CP110 removal and ciliogenesis. TTBK2 can phosphorylate CEP164 and CEP97 and inhibits the CEP164-Dishevelled-3 interaction in a kinase activity-dependent manner. |
Co-immunoprecipitation, domain mutagenesis (SxIP and proline-rich motif mutants), rescue experiments in TTBK2-depleted cells, in vitro kinase assays |
Genes to cells : devoted to molecular & cellular mechanisms |
High |
25297623
|
| 2015 |
TTBK2 acts as an EB1/3-binding plus-end tracking protein (+TIP) and phosphorylates the MT-depolymerizing kinesin KIF2A at S135 in an EB1/3-dependent fashion, inactivating KIF2A's MT-depolymerizing activity. TTBK2 depletion reduces MT lifetime and impairs cell migration, phenotypes partially restored by KIF2A co-depletion. |
In vitro kinase assay, phosphosite identification, co-immunoprecipitation, siRNA knockdown, rescue with non-phosphorylatable KIF2A, live-cell imaging of MT dynamics |
The Journal of cell biology |
High |
26323690
|
| 2018 |
TTBK2 phosphorylates TDP-43, and co-expression of tau/TTBK2 or TDP-43/TTBK1 transgenes in C. elegans causes synergistic exacerbation of behavioral abnormalities, increased pathological phosphorylation, aberrant neuronal architecture, and neuron loss. However, the TTBK2/TDP-43 combination showed no exacerbation of TDP-43 proteinopathy-related phenotypes. |
C. elegans transgenic co-expression models, behavioral assays, immunohistochemistry for phosphorylated proteins, neuronal morphology analysis |
Molecular neurodegeneration |
Medium |
29409526
|
| 2018 |
SCA11-associated truncating mutations in TTBK2 act as dominant negative alleles; the resulting truncated protein (TTBK2SCA11) interferes with full-length TTBK2 function in ciliogenesis, decreases cilia number, disrupts ciliary trafficking of Smoothened (SMO), and interrupts Sonic Hedgehog (SHH) signaling. TTBK2 also controls cilia length and stability after cilia initiation. |
Allelic series in mice, conditional genetics, cilia quantification, SHH pathway reporter assays, immunofluorescence of SMO trafficking |
PLoS genetics |
High |
30532139
|
| 2019 |
CEP83 is a bona fide substrate of TTBK2, with four phosphorylation sites characterized. CEP164-dependent recruitment of TTBK2 to distal appendages is required for subsequent CEP83 phosphorylation. TTBK2-dependent CEP83 phosphorylation is important for early ciliogenesis steps including ciliary vesicle docking and CP110 removal. Serum starvation induces TTBK2 redistribution from the periphery toward the root of distal appendages. |
Super-resolution microscopy, biochemical phosphorylation assays, mutagenesis of phosphorylation sites, co-immunoprecipitation, ciliogenesis assays |
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 ciliary trafficking gene Ift88 produces nearly identical cerebellar phenotypes, placing TTBK2 upstream of ciliary signaling in maintaining Purkinje cell integrity. |
Conditional knockout mouse model, behavioral testing, immunofluorescence, genetic epistasis with Ift88 conditional knockout |
eLife |
High |
31934864
|
| 2021 |
CEP164 recruits TTBK2 to centriolar distal appendages through a direct protein-protein interaction. Two ciliopathic mutations in CEP164 compromise this interaction. Binding to CEP164 influences TTBK2 activities. |
Biochemical binding assays, NMR structural analysis, mutagenesis of ciliopathic mutations, functional ciliogenesis assays |
Structure (London, England : 1993) |
High |
34499853
|
| 2022 |
TTBK2 maintains cilium stability through parallel mechanisms: regulating centriolar satellite composition, maintaining basal body pools of intraflagellar transport (IFT) proteins, and stabilizing axonemal microtubule modifications. Loss of TTBK2 after cilia formation results in increased cilia breaks and eventual cilia loss within 48-72 hours; cilia loss was delayed by inhibitors of actin-based trafficking. |
Conditional deletion in mouse embryonic fibroblasts, immunofluorescence, quantitative analysis of cilia length and frequency, pharmacological inhibition of actin trafficking |
Molecular biology of the cell |
Medium |
36322399
|
| 2016 |
TTBK2 down-regulates glutamate receptor GluK2 activity by decreasing GluK2 protein abundance at the cell membrane via RAB5-dependent endocytosis. This effect requires a kinase-independent function of full-length TTBK2, as truncated TTBK2(450) and kinase-dead mutants did not reduce GluK2 surface expression. |
Xenopus oocyte expression system, dual electrode voltage clamp, confocal microscopy of EGFP-tagged GluK2, dominant-negative RAB5 rescue experiment |
Cellular physiology and biochemistry |
Medium |
27607061
|
| 2023 |
TTBK2 kinase inhibition by small molecule compound 10 (indolyl pyrimidinamine) significantly reduces primary cilia formation on human iPSCs and phenocopies TTBK2 knockout, confirming TTBK2 kinase activity is required for ciliogenesis. |
Chemical tool compound engagement assay in cells, iPSC cilia quantification, TTBK2 knockout comparison |
Scientific reports |
Medium |
37059819
|
| 2024 |
TTBK2 stabilizes primary cilia in granule neuron progenitors (GNPs) by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. The E3 ubiquitin ligase HUWE1 targets TTBK2 for degradation at the centrosome to facilitate primary cilia disassembly and GNP differentiation. TTBK2 depletion inhibits SHH-type medulloblastoma proliferation. |
Co-immunoprecipitation, ubiquitination assays, conditional KO mouse models, GNP proliferation assays, immunofluorescence |
Cell death and differentiation |
High |
38879724
|
| 2023 |
SCA11-associated TTBK2 truncation variants contain a bona fide peroxisomal targeting signal type 1 (PTS1). Expression of these truncated proteins in RPE1 cells reduces peroxisome numbers, disrupts peroxisome fission pathways, and impairs ciliary trafficking of Smoothened (SMO) upon SHH signaling activation. |
Expression of SCA11-associated truncated TTBK2 constructs in RPE1 cells, peroxisome quantification, immunofluorescence of SMO trafficking, peroxisome fission assays |
bioRxivpreprint |
Medium |
36778451
|
| 2025 |
CEP164 undergoes phase separation with TTBK2 through multivalent electrostatic interactions involving CEP164's intrinsically disordered region. These phase separation-based condensates facilitate efficient recruitment of TTBK2 to distal appendages to initiate ciliogenesis. |
In vitro phase separation assays, live-cell imaging of condensates, mutagenesis of electrostatic interaction sites, ciliogenesis rescue assays |
Cell reports |
Medium |
40483689
|
| 2025 |
TTBK2 kinase activity and its interaction with CEP164 are required for recruitment of IFT machinery components (IFT-A, IFT-B, and dynein-2 complexes) to the mother centriole and for CP110 removal. CEP164 homodimerization via its central coiled-coil region is necessary for TTBK2 recruitment, which is in turn required for IFT machinery recruitment. CP110 removal is not always coupled with IFT protein recruitment. |
CEP164-KO and TTBK2-KO cell lines, chimeric construct rescue experiments, immunofluorescence of IFT components and CP110 |
Molecular biology of the cell |
High |
40305080
|
| 2025 |
A missense variant in the TTBK2 kinase domain (L209F) reduces TTBK2 protein levels, impairs kinase activity toward TDP-43, alters cytoskeleton-related protein levels, and dysregulates phosphoproteomic pathways linked to cytoskeletal organization, protein degradation, and TGF-β signaling. |
CRISPR/Cas9 knock-in cell model, phosphoproteomics, Western blot, in vitro kinase assay toward TDP-43 |
Scientific reports |
Medium |
41422144
|
| 2025 |
In mouse testes, TTBK2 co-localizes with α-tubulin in the manchette during spermatogenesis. Knockdown of Ttbk2 causes sperm tail deformity, reduced forward motility, and disorganized axonemal microtubule structure. Ttbk2 knockdown downregulates CEP164, CEP83, and IFT88 expression, linking TTBK2 to sperm flagella formation. |
Intratesticular injection knockdown, transmission electron microscopy, immunofluorescence co-localization, RT-qPCR and Western blot for downstream targets |
Molecular human reproduction |
Medium |
40581359
|
| 2024 |
TTBK2 T3290C (missense) mutation reduces binding affinity to CEP164 and impairs cilia formation in mouse embryonic fibroblasts, but does not affect TTBK2 protein expression or enzymatic activity. |
Co-immunoprecipitation, in vitro kinase assay, cilia formation assay in transfected MEFs, Western blot from patient lymphocytes |
Translational neuroscience |
Medium |
39380965
|