Bloem L J, Pickard T R, Acton S, Donoghue M, Beavis R C, Knierman M D, Wang X
Cardiovascular Discovery Research, Eli Lilly and Company, Indianapolis, IN 46285, USA.
J Mol Cell Cardiol. 2001 Sep;33(9):1739-50. doi: 10.1006/jmcc.2001.1437.
Hypertrophy is an adaptive response of the heart to myocardial injury or hemodynamic overload that may progress and contribute to cardiac decompensation and eventually to heart failure. The signaling pathways controlling this response in the cardiac myocyte are poorly understood. A data mining effort of a human failed heart cDNA library was undertaken in an effort to identify novel signaling molecules involved in cardiac hypertrophy. This effort identified a novel kinase (MLK7) homologous to the mixed lineage kinase family of proteins. The mixed lineage kinases are mitogen-activated protein kinase kinase kinases (MAPKKKs) which activate stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase pathways. They contain a catalytic domain with homology to both serine/threonine and tyrosine-specific kinases and a dual leucine zipper. MLK7 is identical to leucine zipper and sterile-alpha motif protein kinase (ZAK) through the leucine zipper domain but has a completely divergent COOH-terminus and shares approximately 40% homology with the other MLKs overall. Expression of MLK7 mRNA is most abundant in skeletal muscle and heart, with expression restricted to the cardiac myocyte. The recombinant histidine tagged MLK7 expressed and purified from insect cells exhibited serine/threonine kinase activity in vitro with myelin basic protein as substrate. When expressed in cardiac myocytes, MLK7 activated SAPK/JNK1, and ERK and p38 to a lesser extent. Additionally, MLK7 altered fetal gene expression and increased protein synthesis in cardiac myocytes. These data suggest that MLK7 is a new member of the mixed lineage kinase family that modulates cardiac SAPK/JNK pathway and may play a role in cardiac hypertrophy and progression to heart failure.
肥大是心脏对心肌损伤或血流动力学过载的一种适应性反应，这种反应可能会进展并导致心脏失代偿，最终发展为心力衰竭。目前对心肌细胞中控制这种反应的信号通路了解甚少。为了鉴定参与心肌肥大的新信号分子，我们对一个人类衰竭心脏的cDNA文库进行了数据挖掘。这项工作鉴定出一种与混合谱系激酶家族蛋白同源的新型激酶（MLK7）。混合谱系激酶是丝裂原活化蛋白激酶激酶激酶（MAPKKKs），可激活应激激活蛋白激酶/c-Jun N末端激酶（SAPK/JNK）和p38激酶通路。它们含有一个与丝氨酸/苏氨酸激酶和酪氨酸特异性激酶均具有同源性的催化结构域以及一个双亮氨酸拉链。MLK7通过亮氨酸拉链结构域与亮氨酸拉链和无活性α基序蛋白激酶（ZAK）相同，但具有完全不同的COOH末端，与其他MLK总体上具有约40%的同源性。MLK7 mRNA在骨骼肌和心脏中表达最为丰富，且表达仅限于心肌细胞。从昆虫细胞中表达并纯化的重组组氨酸标记的MLK7在体外以髓鞘碱性蛋白为底物表现出丝氨酸/苏氨酸激酶活性。当在心肌细胞中表达时，MLK7激活了SAPK/JNK1，对ERK和p38的激活程度较小。此外，MLK7改变了胎儿基因表达并增加了心肌细胞中的蛋白质合成。这些数据表明，MLK7是混合谱系激酶家族的一个新成员，可调节心脏SAPK/JNK通路，并可能在心肌肥大和向心力衰竭的进展中发挥作用。
