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The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover
Abstract
The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.
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Cites
Identification of ubiquitin ligases required for skeletal muscle atrophy.
Bodine, S. C., Latres, E., Baumhueter, S., Lai, V. K.-M., Nunez, L., Clarke, B. A., Poueymirou, W. T., Panaro, F. J., Na, E., Dharmarajan, K., et al. (2001) · Science · doi:10.1126/science.1065874 · Cited by 3,521
Cited by
Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus
Wang, N., Tytell, J. D., & Ingber, D. E. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2594 · Cited by 1,762
Truncations of titin causing dilated cardiomyopathy
Herman, D. S., Lam, L., Taylor, M. R. G., Wang, L., Teekakirikul, P., Christodoulou, D., Conner, L., DePalma, S. R., McDonough, B., Sparks, E., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1110186 · Cited by 1,485
A Role for NBR1 in Autophagosomal Degradation of Ubiquitinated Substrates
Kirkin, V., Lamark, T., Sou, Y.-S., Bjørkøy, G., Nunn, J. L., Bruun, J.-A., Shvets, E., McEwan, D. G., Clausen, T. H., Wild, P., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.01.020 · Cited by 1,065
Rogov, V., Dötsch, V., Johansen, T., & Kirkin, V. (2014) · Molecular Cell · doi:10.1016/j.molcel.2013.12.014 · Cited by 992
Appreciating force and shape—the rise of mechanotransduction in cell biology
Iskratsch, T., Wolfenson, H., & Sheetz, M. P. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3903 · Cited by 798
Metadata
- Authors
- Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edström, L., Ehler, E., Udd, B., & Gautel, M.
- Venue
- Science
- Published
- 2005-06-10
- Volume
- 308
- Issue
- 5728
- Pages
- 1599-1603
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2122967682
- Cited by
- 593
- References
- 1
- FWCI
- 15.21
- Type
- journal article
- Language
- en
- Open access
- closed
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- Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edström, L., Ehler, E., Udd, B., & Gautel, M. (2005). The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover. Science. https://doi.org/10.1126/science.1110463
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