Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11

Houlden, Henry; Johnson, Janel O.; Gardner‐Thorpe, Christopher; Lashley, Tammaryn; Hernandez, Dena G.; Worth, Paul; Singleton, Andrew B.; Hilton, David A.; Holton, Janice L.; Révész, Tamás; Davis, Mary B.; Giunti, Paola; Wood, Nicholas W.

doi:10.1038/ng.2007.43

Cited by 186 publications

(223 citation statements)

References 14 publications

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“…Conversely, truncating mutations in human TTBK2 were identified as causative for the neurodegenerative disorder spinocerebellar ataxia type 11 (36,54). Our domain-mapping experiments predict that the longest ataxia-associated TTBK2 truncation described, 450X (36), is unable to form a stable complex with Cep164 (Figs. 2H and 3E).…”

Section: Discussionmentioning

confidence: 99%

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Cep164 triggers ciliogenesis by recruiting Tau tubulin kinase 2 to the mother centriole

Čajánek

Nigg

2014

Proc. Natl. Acad. Sci. U.S.A.

159

219

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Primary cilia play critical roles in development and disease. Their assembly is triggered by mature centrioles (basal bodies) and requires centrosomal protein 164kDa (Cep164), a component of distal appendages. Here we show that loss of Cep164 leads to early defects in ciliogenesis, reminiscent of the phenotypic consequences of mutations in TTBK2 (Tau tubulin kinase 2). We identify Cep164 as a likely physiological substrate of TTBK2 and demonstrate that Cep164 and TTBK2 form a complex. We map the interaction domains and demonstrate that complex formation is crucial for the recruitment of TTBK2 to basal bodies. Remarkably, ciliogenesis can be restored in Cep164-depleted cells by expression of chimeric proteins in which TTBK2 is fused to the C-terminal centrioletargeting domain of Cep164. These findings indicate that one of the major functions of Cep164 in ciliogenesis is to recruit active TTBK2 to centrioles. Once positioned, TTBK2 then triggers key events required for ciliogenesis, including removal of CP110 and recruitment of intraflagellar transport proteins. In addition, our data suggest that TTBK2 also acts upstream of Cep164, contributing to the assembly of distal appendages.primary cilium | centrosome

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Section: Discussionmentioning

confidence: 99%

“…These include Nek1 and Nek8, two members of the family of NIMA-related kinases (33,34), and Tau Tubulin Kinase 2 (TTBK2), a member of the casein kinase 1 family (35)(36)(37).…”

mentioning

confidence: 99%

Cep164 triggers ciliogenesis by recruiting Tau tubulin kinase 2 to the mother centriole

Čajánek

Nigg

2014

Proc. Natl. Acad. Sci. U.S.A.

159

219

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“…These proteins include tau-tubulin-associated kinase 2 (SCA11), α1 subunit of the P/Q-type calcium channel (SCA6), regulatory subunit of the protein phosphatase PP2A (SCA12) and fibroblast growth factor 14 (SCA27) (Holmes et al, 2001;Houlden et al, 2007;van de Leemput et al, 2007;van Swieten et al, 2003;Zhuchenko et al, 1997). Future research is required to determine whether these different proteins are components of shared signaling routes or even are linked within one common signaling cascade that underlies SCA disease in general.…”

Section: Discussionmentioning

confidence: 99%

PKCγ mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling

Verbeek

Goedhart

Bruinsma

et al. 2008

Journal of Cell Science

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Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disorder caused by mutations in the neuronal-specific protein kinase C gamma (PKCγ) gene. Since most mutations causing SCA14 are located in the PKCγ C1B regulatory subdomain, we investigated the impact of three C1B mutations on the intracellular kinetics, protein conformation and kinase activity of PKCγ in living cells. SCA14 mutant PKCγ proteins showed enhanced phorbol-ester-induced kinetics when compared with wild-type PKCγ. The mutations led to a decrease in intramolecular FRET of PKCγ, suggesting that they `open' PKCγ protein conformation leading to unmasking of the phorbol ester binding site in the C1 domain. Surprisingly, SCA14 mutant PKCγ showed reduced kinase activity as measured by phosphorylation of PKC reporter MyrPalm-CKAR, as well as downstream components of the MAPK signaling pathway. Together, these results show that SCA14 mutations located in the C1B subdomain `open' PKCγ protein conformation leading to increased C1 domain accessibility, but inefficient activation of downstream signaling pathways.

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“…Mael connects with Cdan1 and Ttbk2 in M m -M f and with Stk31 in M m -M f -H f . Mutations in Cdan1 cause congenital dyserythropoietic anemia type I, while mutations in Ttbk2 lead to the neurodegenerative disease spinocerebellar ataxia type 11 (Dgany et al 2002, Houlden et al 2007. STK31 is a serine-threonine kinase, which displays testis-specific expression as well as high expression in colorectal cancer samples (Yokoe et al 2008).…”

Section: Prediction Of Novel Meiotic Genes From Conserved Co-expressimentioning

confidence: 99%

Mammalian meiosis is more conserved by sex than by species: conserved co-expression networks of meiotic prophase

Li²

2011

Reproduction

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Despite the importance of meiosis to human reproduction, we know remarkably little about the genes and pathways that regulate meiotic progression through prophase in any mammalian species. Microarray expression profiles of mammalian gonads provide a valuable resource for probing gene networks. However, expression studies are confounded by mixed germ cell and somatic cell populations in the gonad and asynchronous germ cell populations. Further, widely used clustering methods for analyzing microarray profiles are unable to prioritize candidate genes for testing. To derive a comprehensive understanding of gene expression in mammalian meiotic prophase, we constructed conserved co-expression networks by linking expression profiles of male and female gonads across mouse and human. We demonstrate that conserved gene co-expression dramatically improved the accuracy of detecting known meiotic genes compared with using co-expression in individual studies. Interestingly, our results indicate that meiotic prophase is more conserved by sex than by species. The co-expression networks allowed us to identify genes involved in meiotic recombination, chromatin cohesion, and piRNA metabolism. Further, we were able to prioritize candidate genes based on quantitative co-expression links with known meiotic genes. Literature studies of these candidate genes suggest that some are human disease genes while others are associated with mammalian gonads. In conclusion, our co-expression networks provide a systematic understanding of cross-sex and cross-species conservations observed during meiotic prophase. This approach further allows us to prioritize candidate meiotic genes for in-depth mechanistic studies in the future.

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Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11

Cited by 186 publications

References 14 publications

Cep164 triggers ciliogenesis by recruiting Tau tubulin kinase 2 to the mother centriole

Cep164 triggers ciliogenesis by recruiting Tau tubulin kinase 2 to the mother centriole

PKCγ mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling

Mammalian meiosis is more conserved by sex than by species: conserved co-expression networks of meiotic prophase

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