Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase 
whose biological function remains largely unknown. We have recently shown that 
TNNI3K expression greatly accelerates cardiac dysfunction in mouse models of 
cardiomyopathy, indicating an important role in modulating disease progression. 
To further investigate TNNI3K kinase activity in vivo, we have generated 
transgenic mice expressing both wild-type and kinase-dead versions of the human 
TNNI3K protein. Importantly, we show that the increased TNNI3K kinase activity 
induces mouse cardiac remodeling, and its kinase activity promotes accelerated 
disease progression in a left-ventricular pressure overload model of mouse 
cardiomyopathy. Using an in vitro kinase assay and proteomics analysis, we show 
that TNNI3K is a dual-function kinase with Tyr and Ser/Thr kinase activity. 
TNNI3K expression induces a series of cellular and molecular changes, including 
a reduction of sarcomere length and changes in titin isoform composition, which 
are indicative of cardiac remodeling. Using antisera to TNNI3K, we show that 
TNNI3K protein is located at the sarcomere Z disc. These combined data suggest 
that TNNI3K mediates cell signaling to modulate cardiac response to stress.