ArticleOpen biology2014
Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line.
Article in Open biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation.Circulation. Genomic and precision medicine · 2025Pooled it
- The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch.eLife · 2026Article
- Titin's P-zone domains A164-167 are essential for thick filament structural arrangement.The Journal of general physiology · 2026Article
- The roles of the microtubule cytoskeletal network in cardiac mechanobiology.Journal of cell science · 2026Review
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Molecular identifiers of the evolutionarily conserved titin pseudokinase.The Biochemical journal · 2026Article
- Mechanically knocking out titin reveals protein tension loss as a trigger of muscle disease.Nature biomedical engineering · 2025Article
- HCM-Associated MuRF1 Variants Compromise Ubiquitylation and Are Predicted to Alter Protein Structure.International journal of molecular sciences · 2025Article
- Illuminating understudied kinases: a generalizable biosensor development method applied to protein kinase N.Communications biology · 2025Article
- Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies.Scientific reports · 2024Review
- A PAX6-regulated receptor tyrosine kinase pairs with a pseudokinase to activate immune defense upon oomycete recognition inProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation.Journal of structural biology · 2023Article
- Pathogenesis of Cardiomyopathy Caused by Variants inCirculation · 2022Article
- Titin (TTN): from molecule to modifications, mechanics, and medical significance.Cardiovascular research · 2022Review
- DCLK1 autoinhibition and activation in tumorigenesis.Innovation (Cambridge (Mass.)) · 2022Article
- Titin kinase ubiquitination aligns autophagy receptors with mechanical signals in the sarcomere.EMBO reports · 2021Article
- Tools for studying and modulating (cardiac muscle) cell mechanics and mechanosensing across the scales.Biophysical reviews · 2021Review
- Conformational changes in twitchin kinase in vivo revealed by FRET imaging of freely movingeLife · 2021Article
- Titin M-line insertion sequence 7 is required for proper cardiac function in mice.Journal of cell science · 2021Article
- Why exercise builds muscles: titin mechanosensing controls skeletal muscle growth under load.Biophysical journal · 2021Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Striated muscle tissues undergo adaptive remodelling in response to mechanical load. This process involves the myofilament titin and, specifically, its kinase domain (TK; titin kinase) that translates mechanical signals into regulatory pathways of gene expression in the myofibril. TK mechanosensing appears mediated by a C-terminal regulatory tail (CRD) that sterically inhibits its active site. Allegedly, stretch-induced unfolding of this tail during muscle function releases TK inhibition and leads to its catalytic activation. However, the cellular pathway of TK is poorly understood and substrates proposed to date remain controversial. TK's best-established substrate is Tcap, a small structural protein of the Z-disc believed to link TK to myofibrillogenesis. Here, we show that TK is a pseudokinase with undetectable levels of catalysis and, therefore, that Tcap is not its substrate. Inactivity is the result of two atypical residues in TK's active site, M34 and E147, that do not appear compatible with canonical kinase patterns. While not mediating stretch-dependent phospho-transfers, TK binds the E3 ubiquitin ligase MuRF1 that promotes sarcomeric ubiquitination in a stress-induced manner. Given previous evidence of MuRF2 interaction, we propose that the cellular role of TK is to act as a conformationally regulated scaffold that functionally couples the ubiquitin ligases MuRF1 and MuRF2, thereby coordinating muscle-specific ubiquitination pathways and myofibril trophicity. Finally, we suggest that an evolutionary dichotomy of kinases/pseudokinases has occurred in TK-like kinases, where invertebrate members are active enzymes but vertebrate counterparts perform their signalling function as pseudokinase scaffolds.
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