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The kinase domain of titin controls muscle gene expression and protein turnover.

Science (New York, N.Y.) | Jun 10, 2005

http://www.ncbi.nlm.nih.gov/pubmed/15802564

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.

Pubmed ID: 15802564 RIS Download

Mesh terms: Amino Acid Sequence | Amino Acid Substitution | Animals | Catalytic Domain | Cell Line | Cell Nucleus | Connectin | Gene Expression Regulation | Heat-Shock Proteins | Humans | Ligands | Mice | Mice, Inbred C3H | Molecular Sequence Data | Muscle Proteins | Muscle, Skeletal | Muscular Diseases | Mutation | Myocytes, Cardiac | Protein Binding | Protein Conformation | Protein Kinases | Protein Structure, Tertiary | Proteins | Rats | Respiratory Insufficiency | Sarcomeres | Serum Response Factor | Signal Transduction | Two-Hybrid System Techniques | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: Medical Research Council, Id: G0200496(63216)
  • Agency: Medical Research Council, Id: G0300213
  • Agency: British Heart Foundation, Id: PG/03/049/15364

BioGRID (Data, Interactions)

Comparative Toxicogenomics Database (Data, Disease Annotation)

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