Kovacic-Milivojević Branka, Damsky Caroline C, Gardner David G, Ilić Dusko
Metabolic Research Unit, University of California, San Francisco, CA 94143, USA.
Cell Mol Biol Lett. 2002;7(2):323-9.
The vertebrate heart responds to hemodynamic load with the enlargement of postmitotic, terminally differentiated cardiac myocytes. Such hypertrophic changes are characterized by alterations in sarcomeric organization and gene expression. Previously, we established a role for a nonreceptor tyrosine kinase, focal adhesion kinase, in signaling the changes in cytoskeletal organization associated with hypertrophy. Here, we report on data supporting a key role for p130Cas in this process. In neonatal cardiac myocytes FAK, Cas and paxillin are located in sarcomeric Z-lines, suggesting that the Z-line is an important signaling locus in these cells. The expression of different Cas mutants results in a nearly complete loss of sarcomeric organization in these myocytes. Moreover, expression of the C-terminal focal adhesion-targeting domain of FAK both disrupted sarcomeric organization and interfered with the localization of endogenous Cas to Z-lines. These findings suggest that the association of FAK and Cas and the preservation of multiple protein-interaction motifs of Cas are required for the correct assembly of sarcomeres in cardiac myocytes.
脊椎动物的心脏会通过有丝分裂后终末分化的心肌细胞增大来应对血流动力学负荷。这种肥大性变化的特征是肌节组织和基因表达的改变。此前，我们确定了一种非受体酪氨酸激酶——粘着斑激酶在信号传导与肥大相关的细胞骨架组织变化中所起的作用。在此，我们报告支持p130Cas在此过程中起关键作用的数据。在新生心肌细胞中，FAK、Cas和桩蛋白定位于肌节Z线，这表明Z线是这些细胞中的一个重要信号位点。不同Cas突变体的表达导致这些心肌细胞中肌节组织几乎完全丧失。此外，FAK的C末端粘着斑靶向结构域的表达既破坏了肌节组织，又干扰了内源性Cas定位于Z线。这些发现表明，FAK与Cas的结合以及Cas多个蛋白质相互作用基序的保留是心肌细胞中肌节正确组装所必需的。
