Titin is a giant protein found in vertebrate cardiac and skeletal muscle that spans the entire half sarcomere. Different parts of the titin polypeptide perform different functions. The N-terminal region of titin contains multiple binding sites for Z-disc proteins and appears to regulate Z-disc assembly. Titin's I-band region contains spring elements responsible for the elastic response of the stretched sarcomere. Titin's A-band region contains immunoglobulin (Ig) and fibronectin type 3 (Fn3) domains that are arranged in regular patterns that provide multiple binding sites for other thick filament proteins. This region of titin may serve as a molecular ruler in charge of assembly and length control of the thick filament. The approximately 200 KDa C-terminal region of titin anchors titin within the M-line lattice and contains a kinase domain with serine/threonine specificity. The function of the kinase domain is unknown. The titin kinase is highly conserved in vertebrates and the titin-like proteins found in invertebrates contain homologous kinase domains, suggesting that the titin kinase performs functions of critical importance. The long-term goal of this work is to establish the roles of the titin kinase in muscle function and muscle and cardiovascular disease. To lay the groundwork for this I have used gene targeting and developed conventional and Cre-inducible titin kinase knock-out mouse models. Furthermore, I will investigate a novel titin kinase binding protein named MURF. In the proposed research I will apply these new tools, using a multidisciplinary approach, and investigate the role of the titin kinase in muscle.
My aim i s to identify the titin substrate and study the relation between MURFs and titin kinase function. I will test the hypothesis that the titin kinase is critical for growth, division and survival of cells and that the kinase is important for in vivo muscle function.
| Raddatz, Katy; Albrecht, Dirk; Hochgrafe, Falko et al. (2008) A proteome map of murine heart and skeletal muscle. Proteomics 8:1885-97 |
| Granzier, Henk; Radke, Michael; Royal, Joseph et al. (2007) Functional genomics of chicken, mouse, and human titin supports splice diversity as an important mechanism for regulating biomechanics of striated muscle. Am J Physiol Regul Integr Comp Physiol 293:R557-67 |
| Peng, Jun; Raddatz, Katy; Molkentin, Jeffery D et al. (2007) Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region. Circulation 115:743-51 |
| Peng, J; Raddatz, K; Labeit, S et al. (2005) Muscle atrophy in titin M-line deficient mice. J Muscle Res Cell Motil 26:381-8 |
| Witt, Christian C; Ono, Yasuko; Puschmann, Eva et al. (2004) Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling. J Mol Biol 336:145-54 |
