Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

• Published in: Science (American Association for the Advancement of Science) 2005-06, Vol.308 (5728), p.1599-1603
• Main Authors: Lange, Stephan, Xiang, Fengqing, Yakovenko, Andrey, Vihola, Anna, Hackman, Peter, Rostkova, Elena, Kristensen, Jakob, Brandmeier, Birgit, Franzen, Gereon, Hedberg, Birgitta, Gunnarsson, Lars Gunnar, Hughes, Simon M, Marchand, Sylvie, Sejersen, Thomas, Richard, Isabelle, Edström, Lars, Ehler, Elisabeth, Udd, Bjarne, Gautel, Mathias
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Biological and medical sciences; Catalytic Domain; Cell Line; Cell lines; Cell Nucleus - metabolism; Connectin; Disease; Gene expression; Gene Expression Regulation; General aspects; Genes; Genetic mutation; Heat-Shock Proteins - metabolism; Humans; Individualized Instruction; Interaction Process Analysis; Intracellular Signaling Peptides and Proteins; Ligands; Medical sciences; Mice; Mice, Inbred C3H; Molecular Sequence Data; Muscle Proteins - chemistry; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscles; Muscular diseases; Muscular Diseases - genetics; Muscular system; Mutation; Myocytes, Cardiac - metabolism; Protein Binding; Protein Conformation; Protein Kinases - chemistry; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Structure, Tertiary; Proteins; Proteins - metabolism; Rats; Research Article; Respiratory Insufficiency - genetics; Respiratory Insufficiency - metabolism; Sarcomeres; Sarcomeres - metabolism; Screening Tests; Sequestosome-1 Protein; Serum Response Factor - metabolism; Signal Transduction; Skeletal muscle; Two-Hybrid System Techniques; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1110463

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.