Cohen O, Kimchi A
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Cell Death Differ. 2001 Jan;8(1):6-15. doi: 10.1038/sj.cdd.4400794.
DAP-kinase is a pro-apoptotic Ca(2+) calmodulin-regulated serine/threonine kinase that participates in a wide array of apoptotic systems initiated by interferon-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. It was isolated by an unbiased functional approach to gene cloning aimed at hitting central mediators of the apoptotic process. This 160 Kd protein kinase is localized to actin microfilaments and carries interesting modules such as ankyrin repeats and the death domain. The death promoting effects of DAP-kinase depend on its intact catalytic activity, the correct intracellular localization, and on the presence of the death domain. A few mechanisms restrain the killing effects of the protein in healthy cells. The enzyme's active site is negatively controlled by an adjacent CaM regulatory domain whose effect is relieved by binding to Ca(2+)-activated calmodulin. A second mode of autoinhibition engages the serine-rich C-terminal tail, spanning the last 17 amino acids of the protein. A link between DAP-kinase and cancer has been established. It was found that the mRNA and protein expression is frequently lost in various human cancer cell lines. Analysis of the methylation status of DAP-kinase's 5' UTR in DNA extracted from fresh tumor samples, showed high incidence of hypermethylation in several human carcinomas and B cell malignancies. The anti-tumorigenic effect of DAP-kinase was also studied experimentally in mouse model systems where the re-introduction of DAP-kinase into highly metastatic mouse lung carcinoma cells who had lost the protein, strongly reduced their metastatic capacity. Thus, it appears that loss of DAP-kinase confers a selective advantage to cancer cells and may play a causative role in tumor progression. A few novel kinases sharing high homology in their catalytic domains with DAP-kinase have been recently identified constituting altogether a novel family of death promoting serine/threonine kinases.
DAP激酶是一种促凋亡的钙调蛋白调节的丝氨酸/苏氨酸激酶，参与由干扰素-γ、肿瘤坏死因子-α、活化的Fas以及从细胞外基质脱离引发的多种凋亡系统。它是通过一种无偏向性的基因克隆功能方法分离得到的，旨在找到凋亡过程的核心介质。这种160千道尔顿的蛋白激酶定位于肌动蛋白微丝，并带有诸如锚蛋白重复序列和死亡结构域等有趣的模块。DAP激酶的促死亡作用取决于其完整的催化活性、正确的细胞内定位以及死亡结构域的存在。一些机制限制了该蛋白在健康细胞中的杀伤作用。该酶的活性位点受到相邻钙调蛋白调节结构域的负调控，与钙激活的钙调蛋白结合可解除这种调控作用。第二种自抑制模式涉及富含丝氨酸的C末端尾巴，该尾巴跨越蛋白质的最后17个氨基酸。DAP激酶与癌症之间的联系已经确立。研究发现，在各种人类癌细胞系中，其mRNA和蛋白表达常常缺失。对从新鲜肿瘤样本中提取的DNA中DAP激酶5'非翻译区的甲基化状态分析表明，在几种人类癌和B细胞恶性肿瘤中，高甲基化发生率很高。在小鼠模型系统中也通过实验研究了DAP激酶的抗肿瘤作用，将DAP激酶重新导入已丢失该蛋白的高转移性小鼠肺癌细胞中，可强烈降低其转移能力。因此，似乎DAP激酶的缺失赋予癌细胞一种选择性优势，并可能在肿瘤进展中起因果作用。最近已鉴定出一些在催化结构域与DAP激酶具有高度同源性的新型激酶，它们共同构成了一个新的促死亡丝氨酸/苏氨酸激酶家族。
