The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

S Lange; F Xiang; A Yakovenko; A Vihola; P Hackman; E Rostkova; J Kristensen; B Brandmeier; G Franzen; B Hedberg; L  G Gunnarsson; S  M Hughes; S Marchand; T Sejersen; I Richard; L Edstrom; E Ehler; B Udd; M Gautel

doi:10.1126/science.1110463

The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

S Lange, F Xiang, A Yakovenko, A Vihola, P Hackman, E Rostkova, J Kristensen, B Brandmeier, G Franzen, B Hedberg, L G Gunnarsson, S M Hughes, S Marchand, T Sejersen, I Richard, L Edstrom, E Ehler, B Udd, M Gautel

Research output: Contribution to journal › Article › peer-review

482 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1599 - 1603
Number of pages	5
Journal	Science
Volume	308
Issue number	5728
DOIs	https://doi.org/10.1126/science.1110463
Publication status	Published - 10 Jun 2005

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Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edstrom, L., Ehler, E., Udd, B., & Gautel, M. (2005). The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover. Science, 308(5728), 1599 - 1603. https://doi.org/10.1126/science.1110463

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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.",

author = "S Lange and F Xiang and A Yakovenko and A Vihola and P Hackman and E Rostkova and J Kristensen and B Brandmeier and G Franzen and B Hedberg and Gunnarsson, {L G} and Hughes, {S M} and S Marchand and T Sejersen and I Richard and L Edstrom and E Ehler and B Udd and M Gautel",

year = "2005",

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doi = "10.1126/science.1110463",

language = "English",

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Lange, S, Xiang, F, Yakovenko, A, Vihola, A, Hackman, P, Rostkova, E, Kristensen, J, Brandmeier, B, Franzen, G, Hedberg, B, Gunnarsson, LG, Hughes, SM, Marchand, S, Sejersen, T, Richard, I, Edstrom, L, Ehler, E, Udd, B & Gautel, M 2005, 'The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover', Science, vol. 308, no. 5728, pp. 1599 - 1603. https://doi.org/10.1126/science.1110463

TY - JOUR

T1 - The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

AU - Lange, S

AU - Xiang, F

AU - Yakovenko, A

AU - Vihola, A

AU - Hackman, P

AU - Rostkova, E

AU - Kristensen, J

AU - Brandmeier, B

AU - Franzen, G

AU - Hedberg, B

AU - Gunnarsson, L G

AU - Hughes, S M

AU - Marchand, S

AU - Sejersen, T

AU - Richard, I

AU - Edstrom, L

AU - Ehler, E

AU - Udd, B

AU - Gautel, M

PY - 2005/6/10

Y1 - 2005/6/10

N2 - 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.

AB - 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.

U2 - 10.1126/science.1110463

DO - 10.1126/science.1110463

M3 - Article

SN - 0036-8075

VL - 308

SP - 1599

EP - 1603

JO - Science

JF - Science

IS - 5728

ER -

The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

Abstract

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