Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis

被引：8

作者：

Bashore, Frances M. M. ^{[1
]}

Marquez, Ariana B. B. ^{[2
]}

Chaikuad, Apirat ^{[3
,4
]}

Howell, Stefanie ^{[1
]}

Dunn, Andrea S. S. ^{[5
]}

Beltran, Alvaro A. A. ^{[2
,6
]}

Smith, Jeffery L. L. ^{[1
]}

Drewry, David H. H. ^{[1
,7
]}

Beltran, Adriana S. S. ^{[2
,8
]}

Axtman, Alison D. D. ^{[1
]}

机构：

[1] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 USA

[2] Univ North Carolina Chapel Hill, Human Pluripotent Cell Core, Chapel Hill, NC 27599 USA

[3] Goethe Univ Frankfurt, Inst Pharmaceut Chem, Max von Laue Str 9, D-60438 Frankfurt, Germany

[4] Goethe Univ Frankfurt, Buchmann Inst Life Sci, Struct Genom Consortium, Max von Laue Strabe 15, D-60438 Frankfurt, Germany

[5] Univ North Carolina Chapel Hill, Dept Comp Sci, Chapel Hill, NC 27599 USA

[6] Univ North Carolina Chapel Hill, Neurosci Ctr, Chapel Hill, NC 27599 USA

[7] Univ North Carolina Chapel Hill, UNC Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA

[8] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA

来源：

SCIENTIFIC REPORTS | 2023年 / 13卷 / 01期

基金：

巴西圣保罗研究基金会; 加拿大创新基金会;

关键词：

PHOSPHORYLATION; IDENTIFICATION; EXPRESSION; INHIBITOR; PIKFYVE; CEP164;

D O I：

10.1038/s41598-023-32854-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact of TTBK1 inhibition in diseases like Alzheimer's disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 knockout in iPSCs, confirming a role for TTBK2 in ciliogenesis.

引用

页数：17

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