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Originally published in Science Express on 31 March 2005
Science 10 June 2005:
Vol. 308. no. 5728, pp. 1599 - 1603
DOI: 10.1126/science.1110463
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Research Articles

The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

Stephan Lange,1,2,3* Fengqing Xiang,4* Andrey Yakovenko,1,2 Anna Vihola,5 Peter Hackman,5 Elena Rostkova,1,2 Jakob Kristensen,1,2 Birgit Brandmeier,1,2 Gereon Franzen,1,2 Birgitta Hedberg,4 Lars Gunnar Gunnarsson,6 Simon M. Hughes,1 Sylvie Marchand,7 Thomas Sejersen,8 Isabelle Richard,7 Lars Edström,4 Elisabeth Ehler,1,2 Bjarne Udd,5,9,10{dagger} Mathias Gautel1,2{dagger}

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.

1 Muscle Signalling and Development, Randall Division, King's College London, London SE1 1UL, UK.
2 Muscle Cell Biology, Cardiovascular Division, King's College London, London SE1 1UL, UK.
3 Institute of Cell Biology, Eidgenössische Technische Hochschule (ETH) Hönggerberg, CH 8093 Zürich, Switzerland.
4 Department of Clinical Neuroscience, Karolinska Institute/Karolinska Hospital, 171 76 Stockholm, Sweden.
5 Folkhälsan Institute of Genetics and Department of Medical Genetics, University of Helsinki, Biomedicum, 00290 Helsinki, Finland.
6 Department of Environmental Medicine, Örebro University Hospital, 70185 Örebro, Sweden.
7 Genethon CNRS UMR8115, 1 Rue de l'Internationale, 91000 Evry, France.
8 Department of Woman and Child Health, Neuropediatric Unit, Astrid Lindgren Children's Hospital, 171 76 Stockholm, Sweden.
9 Department of Neurology, Vasa Central Hospital, 65130 Vasa, Finland.
10 Department of Neurology, Tampere University Hospital, 33520 Tampere, Finland.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: mathias.gautel{at}kcl.ac.uk (M.G.); Bjarne.Udd{at}vshp.fi (B.U.)

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Science. ISSN 0036-8075 (print), 1095-9203 (online)