文章：

癌症中激酶和蛋白酶之间的调控串扰

The regulatory crosstalk between kinases and proteases in cancer

原文发布日期：2010-03-19

DOI: 10.1038/nrc2823

类型: Review Article

开放获取: 否

要点：

1. Protein kinases and proteases are both major classes of cellular enzymes; the kinome and the degradome each include more than 500 genes.
2. Direct interactions between kinases and proteases are frequent, and more than 125 examples of kinases that undergo regulated processing by one or more proteases are currently known. Targets for proteases include kinases in all the major branches of the kinome, as well as atypical protein kinases. Conversely, approximately 150 proteases in all the main families in the degradome are known to be phosphorylated by one or more kinases.
3. Bidirectional kinase–protease interactions have an important role in many cellular processes, including transmembrane signalling, apoptosis and cell migration. Prominent examples include kinase–caspase crosstalk in apoptosis and interactions between deubiquitylases or γ-secretase and receptor tyrosine kinases in cell proliferation and invasion.
4. Kinase–protease interactions are implicated as causal events in disease, and have a particularly important role in cancer. Cell migration and invasion are hallmarks of metastatic cancer, and many kinase–protease interactions are involved in activating these processes in a dysregulated fashion in cancer cells.
5. Clinical implications of kinase–protease crosstalk are emerging. Interplay between ERBB family receptor tyrosine kinases and a disintegrin and metalloproteinase (ADAM) proteases results in the shedding of ERBB2 soluble forms that blunt the efficiency of ERBB2-specific monoclonal antibody therapy in breast cancer. A clinical trial in patients with breast cancer is underway using a combination of an ADAM10 and ADAM17 inhibitor with an ERBB2-specific antibody.
6. Kinase–protease connections are being uncovered at a rapid pace, and their roles in cancer will undoubtedly become increasingly important and offer new opportunities for clinical intervention.

要点翻译：

1. 蛋白激酶与蛋白酶均是细胞酶的主要类别；激酶组与降解组各自包含超过500个基因。
2. 激酶与蛋白酶之间的直接相互作用十分常见，目前已知有125余种激酶会受一种或多种蛋白酶调控加工。蛋白酶的靶标涵盖激酶组所有主要分支中的激酶，也包括非典型蛋白激酶。反之，降解组所有主要家族中约有150种蛋白酶已知会被一种或多种激酶磷酸化。
3. 双向激酶-蛋白酶相互作用在众多细胞进程中具有重要作用，包括跨膜信号传导、细胞凋亡与细胞迁移。典型实例包括细胞凋亡中的激酶-半胱天冬酶交叉对话，以及在细胞增殖和侵袭中去泛素化酶或γ-分泌酶与受体酪氨酸激酶之间的相互作用。
4. 激酶-蛋白酶相互作用被证实是疾病的诱发因素，在癌症中作用尤为关键。细胞迁移与侵袭是转移性癌症的标志特征，而众多激酶-蛋白酶相互作用会以失调方式激活癌细胞中的这些进程。
5. 激酶-蛋白酶交叉对话的临床意义正在显现。ERBB家族受体酪氨酸激酶与去整合素-金属蛋白酶（ADAM）之间的相互作用导致ERBB2可溶性形式脱落，从而削弱了ERBB2特异性单克隆抗体疗法在乳腺癌中的疗效。目前一项针对乳腺癌患者的临床试验正在联合使用ADAM10/ADAM17抑制剂与ERBB2特异性抗体。
6. 激酶-蛋白酶关联正被快速揭示，它们在癌症中的作用必将日益重要，并为临床干预提供新机遇。

英文摘要：

Kinases and proteases are responsible for two fundamental regulatory mechanisms — phosphorylation and proteolysis — that orchestrate the rhythms of life and death in all organisms. Recent studies have highlighted the elaborate interplay between both post-translational regulatory systems. Many intracellular or pericellular proteases are regulated by phosphorylation, whereas multiple kinases are activated or inactivated by proteolytic cleavage. The functional consequences of this regulatory crosstalk are especially relevant in the different stages of cancer progression. What are the clinical implications derived from the fertile dialogue between kinases and proteases in cancer?

摘要翻译： 

激酶和蛋白酶是两种基本调控机制——磷酸化和蛋白水解——的负责者，它们共同 orchestrate（编排）着所有生物体中生命与死亡的节律。近期研究强调了这两种翻译后调控系统之间复杂的相互作用。许多细胞内或细胞周围的蛋白酶受磷酸化调控，而多种激酶则通过蛋白水解切割被激活或失活。这种调控“串扰”的功能后果，在癌症进展的不同阶段尤为关键。那么，激酶与蛋白酶之间“活跃对话”在癌症中的临床意义是什么？

原文链接：

The regulatory crosstalk between kinases and proteases in cancer