title: 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.
authors.affiliation: Muscle Signalling and Development, Randall Division, King's College London, London SE1 1UL, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lange
authors.forename: Fengqing
authors.initials: F
authors.lastname: Xiang
authors.forename: Andrey
authors.initials: A
authors.lastname: Yakovenko
authors.forename: Anna
authors.initials: A
authors.lastname: Vihola
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
authors.forename: Elena
authors.initials: E
authors.lastname: Rostkova
authors.forename: Jakob
authors.initials: J
authors.lastname: Kristensen
authors.forename: Birgit
authors.initials: B
authors.lastname: Brandmeier
authors.forename: Gereon
authors.initials: G
authors.lastname: Franzen
authors.forename: Birgitta
authors.initials: B
authors.lastname: Hedberg
authors.forename: Lars Gunnar
authors.initials: LG
authors.lastname: Gunnarsson
authors.forename: Simon M
authors.initials: SM
authors.lastname: Hughes
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marchand
authors.forename: Thomas
authors.initials: T
authors.lastname: Sejersen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
authors.forename: Lars
authors.initials: L
authors.lastname: Edström
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ehler
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D064211:Connectin; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000235:genetics; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D051381:Rats; D012131:Respiratory Insufficiency / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D064211:Connectin; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D009124:Muscle Proteins; C549756:NBR1 protein, human; C486327:Nbr1 protein, rat; D011506:Proteins; D000071456:Sequestosome-1 Protein; D026362:Serum Response Factor; C491079:Sqstm1 protein, rat; C577285:TTN protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases