Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tau-tubulin kinase (TTBK) belongs to casein kinase superfamily and phosphorylates microtubule-associated protein tau and tubulin. TTBK has two isoforms, TTBK1 and TTBK2, which contain highly homologous catalytic domains but their non-catalytic domains are distinctly different. TTBK1 is expressed specifically in the central nervous system and is involved in phosphorylation and aggregation of tau. TTBK2 is ubiquitously expressed in multiple tissues and genetically linked to spinocerebellar ataxia type 11. TTBK1 directly phosphorylates tau protein, especially at Ser422, and also activates cycline-dependent kinase 5 in a unique mechanism. TTBK1 protein expression is significantly elevated in Alzheimer's disease (AD) brains, and genetic variations of the TTBK1 gene are associated with late-onset Alzheimer's disease in two cohorts of Chinese and Spanish populations. TTBK1 transgenic mice harboring the entire 55-kilobase genomic sequence of human TTBK1 show progression of tau accumulation, neuroinflammation, and neurodegeneration when crossed with tau mutant mice. Our recent study shows that there is a striking switch in mononuclear phagocyte and activation phenotypes in the anterior horn of the spinal cord from alternatively activated (M2-skewed) microglia in P301L tau mutant mice to pro-inflammatory (M1-skewed) infiltrating peripheral monocytes by crossing the tau mice with TTBK1 transgenic mice. TTBK1 is responsible for mediating M1-activated microglia-induced neurotoxicity, and its overexpression induces axonal degeneration in vitro. These studies suggest that TTBK1 is an important molecule for the inflammatory axonal degeneration, which may be relevant to the pathobiology of tauopathy including AD.
Front Mol Neurosci 2014
PMID:Tau-tubulin kinase. 2480 23

Tau-tubulin kinase 1 (TTBK1) is a CNS-specific, kinase that has been implicated in the pathological phosphorylation of tau in Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD). TTBK1 is a challenging therapeutic target because it shares a highly conserved catalytic domain with its homolog, TTBK2, a ubiquitously expressed kinase genetically linked to the disease spinocerebellar ataxia type 11. The present study attempts to elucidate the functional distinctions between the TTBK isoforms and increase our understanding of them as distinct targets for the treatment of neurodegenerative disease. We demonstrate that in cortical neurons, TTBK1, not TTBK2, is the isoform responsible for tau phosphorylation at epitopes enriched in tauopathies such as Serine 422. In addition, although our elucidation of the crystal structure of the TTBK2 kinase domain indicates almost identical structural similarity with TTBK1, biochemical and cellular assays demonstrate that the enzymatic activity of these two proteins is regulated by a combination of unique extra-catalytic sequences and autophosphorylation events. Finally, we have identified an unbiased list of neuronal interactors and phosphorylation substrates for TTBK1 and TTBK2 that highlight the unique cellular pathways and functional networks that each isoform is involved in. This data address an important gap in knowledge regarding the implications of targeting TTBK kinases and may prove valuable in the development of potential therapies for disease.
Cell Mol Neurobiol 2020 May 18
PMID:Mechanisms of Regulation and Diverse Activities of Tau-Tubulin Kinase (TTBK) Isoforms. 3242 73