Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
J Mol Cell Cardiol. 2013 Jan;54:101-11. doi: 10.1016/j.yjmcc.2012.10.004. Epub 2012 Oct 16.
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.
心肌钙蛋白 I 相互作用激酶（TNNI3K）是一种心脏特异性激酶，其生物学功能在很大程度上尚不清楚。我们最近表明，TNNI3K 的表达大大加速了心肌病小鼠模型中的心脏功能障碍，表明其在调节疾病进展方面发挥着重要作用。为了进一步研究 TNNI3K 激酶活性在体内的作用，我们生成了表达野生型和激酶失活型人 TNNI3K 蛋白的转基因小鼠。重要的是，我们表明增加的 TNNI3K 激酶活性诱导了小鼠心脏重构，并且其激酶活性促进了小鼠心肌病左心室压力超负荷模型中疾病的加速进展。通过体外激酶测定和蛋白质组学分析，我们表明 TNNI3K 是一种具有 Tyr 和 Ser/Thr 激酶活性的双功能激酶。TNNI3K 的表达诱导了一系列细胞和分子变化，包括肌节长度的减少和肌联蛋白同工型组成的变化，这表明存在心脏重构。使用针对 TNNI3K 的抗血清，我们表明 TNNI3K 蛋白位于肌节 Z 盘。这些综合数据表明，TNNI3K 通过介导细胞信号转导来调节心脏对压力的反应。
