A proteomics approach to titin kinase mechanosignaling in striated muscle.

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The sarcomeric protein titin is the largest known protein in mammals and mutations in the gene have been recognized as the most common cause of inherited heart disease. Titin was originally discovered as scaffolding protein in striated muscle, with recent evidence suggesting a role in signal transduction: It has been hypothesized that the force dependent interaction of titin’s regulatory and catalytic kinase domain could provide a mechanosensor and tyrosine phosphorylation of the catalytic domain (Y170) an additional level of regulation. The analysis of mutations in patients with hereditary muscle disease has linked titin to hypertrophy/atrophy signaling and we have shown that loss of the kinase region leads to hypertrophic cardiomyopathy. Here, we will establish the molecular pathways relating titin kinase (TK) and hypertrophy/atrophy signaling in striated muscle, building on our strength in proteomics and in generating and analyzing animal models of cardiovascular disease. We will use localization proteomics to probe the environment of the titin kinase domain in vivo and dissect its role in mechanotransduction and hypertrophy signaling. Combined with the knockout (KO) of the catalytic domain and application of different sources of mechanical stress and strain we will elucidate the type of mechanical input that activates the TK followed by a candidate and proteomics approach to analyze the downstream events. This includes the analysis of TK as a hub versus a catalytically active kinase and the differential response to pressure and volume. This research has implications for maintaining muscle mass in immobilized patients or the elderly and for physiological versus pathological hypertrophy of the heart.