Cancer and Human Molecular Genetics Area-Oto-Neurosurgery Research Group, University Hospital La Paz Research Institute (IdiPAZ), Paseo de la Castellana 261, E-28046 Madrid, Spain.
Department of Biology, University of Copenhagen, 13 Universitetsparken, DK-2100 Copenhagen, Denmark.
Int J Mol Sci. 2020 Jan 24;21(3):765. doi: 10.3390/ijms21030765.
Calmodulin (CaM) is the principal Ca sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca concentration within the cell. The Ca/CaM complex as well as Ca-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial-mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.
钙调蛋白（CaM）是所有真核细胞中主要的 Ca 传感器蛋白，它与靶蛋白结合后，将细胞内 Ca 浓度的全局或亚细胞特异性变化编码的信号转导。Ca/CaM 复合物以及无 Ca 的 CaM 调节大量酶、通道、信号转导、衔接和结构蛋白的活性，从而调节所涉及的信号通路的功能，这些信号通路控制多种细胞功能。CaM 通过多种方式控制的基本而重要的细胞功能是细胞运动。在这里，我们讨论了 CaM 依赖性系统在细胞迁移、肿瘤细胞侵袭和转移发展中所涉及的作用。重点介绍了肌球蛋白轻链激酶、CaM 依赖性激酶-II 以及其他 CaM 依赖性激酶催化的磷酸化/去磷酸化事件，以及 CaM 依赖性磷酸酶钙调神经磷酸酶。此外，还将讨论 CaM 调节的小 GTP 酶 Rac1 和 Cdc42（细胞分裂周期蛋白 42）以及 CaM 结合衔接/scaffold 蛋白（如 Grb7（生长因子受体结合蛋白 7）、IQGAP（包含 IQ 基序的 GTP 酶激活蛋白）和 AKAP12（A 激酶锚定蛋白 12）的作用。将讨论癌细胞中负责其与非恶性细胞相比具有更强迁移能力、侵袭相邻正常组织及其全身播散的 CaM 调节机制，包括紧密相关的过程，如上皮-间充质转化和金属蛋白酶的激活。本综述还涵盖了 CaM 在建立远处器官转移灶中的作用。最后，概述了使用 CaM 拮抗剂和其他阻断技术下调 CaM 依赖性系统，以防止癌细胞侵袭和转移发展的作用。
