Journal
SCIENCE
Volume 308, Issue 5728, Pages 1599-1603Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1110463
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Funding
- MRC [G0300213] Funding Source: UKRI
- Medical Research Council [G0300213] Funding Source: researchfish
- British Heart Foundation [PG/03/049/15364] Funding Source: Medline
- Medical Research Council [G0200496(63216), G0300213] Funding Source: Medline
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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.
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