The kinase domain of titin controls muscle gene expression and protein turnover.
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.
Lange
Stephan
S
Muscle Signalling and Development, Randall Division, King's College London, London SE1 1UL, UK.
Xiang
Fengqing
F
Yakovenko
Andrey
A
Vihola
Anna
A
Hackman
Peter
P
Rostkova
Elena
E
Kristensen
Jakob
J
Brandmeier
Birgit
B
Franzen
Gereon
G
Hedberg
Birgitta
B
Gunnarsson
Lars Gunnar
LG
Hughes
Simon M
SM
Marchand
Sylvie
S
Sejersen
Thomas
T
Richard
Isabelle
I
Edström
Lars
L
Ehler
Elisabeth
E
Udd
Bjarne
B
Gautel
Mathias
M
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
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