Xu L H, Yang X, Craven R J, Cance W G
Department of Surgery, University of North Carolina at Chapel Hill School of Medicine, 27599, USA.
Cell Growth Differ. 1998 Dec;9(12):999-1005.
Focal adhesion kinase (FAK) is a tyrosine kinase that is linked to signaling pathways between cells and their extracellular matrix. An alternate transcript of the COOH-terminal region of the FAK gene, called FAK-related nonkinase, has been shown to act as an inhibitor of FAK in chicken embryo fibroblasts. We have designed an analogous segment of human FAK, FAK COOH-terminal domain (FAK-CD), and transfected this construct into human tumor cells. Expression of FAK-CD inhibited cell growth in BT474 human breast cancer cells and C8161 human melanoma cells. To characterize the nature of growth inhibition, we developed an inducible system of FAK-CD expression and demonstrated that the induced FAK-CD protein localized to focal adhesions, causing cellular rounding, an irreversible loss of adhesion, and subsequent cell death. In addition, expression of FAK-CD reduced tyrosine phosphorylation of FAK, suggesting that FAK-CD may be a potent inhibitor of FAK in human tumor cells.
粘着斑激酶（FAK）是一种酪氨酸激酶，与细胞及其细胞外基质之间的信号通路相关。FAK基因COOH末端区域的一种可变转录本，称为FAK相关非激酶，已被证明在鸡胚成纤维细胞中作为FAK的抑制剂发挥作用。我们设计了人FAK的类似片段，即FAK COOH末端结构域（FAK-CD），并将该构建体转染到人肿瘤细胞中。FAK-CD的表达抑制了BT474人乳腺癌细胞和C8161人黑色素瘤细胞的生长。为了表征生长抑制的性质，我们开发了一种FAK-CD表达的诱导系统，并证明诱导的FAK-CD蛋白定位于粘着斑，导致细胞变圆、不可逆的粘附丧失以及随后的细胞死亡。此外，FAK-CD的表达降低了FAK的酪氨酸磷酸化，表明FAK-CD可能是人类肿瘤细胞中FAK的有效抑制剂。
