Ismail Thamir M, Fernig David G, Rudland Philip S, Terry Carla J, Wang Guozheng, Barraclough Roger
Cancer and Polio Research Fund Laboratories, Biosciences Building, University of Liverpool, Liverpool, UK.
Carcinogenesis. 2008 Dec;29(12):2259-66. doi: 10.1093/carcin/bgn217. Epub 2008 Sep 10.
The calcium-binding protein S100A4 can induce a metastatic phenotype in animal model systems and its expression in various human cancers has been shown to be associated with metastasis and reduced patient survival. Using a series of nested deletion mutants, it is now shown that the two C-terminal lysine residues are required for the enhanced metastasis, invasion and migration abilities that S100A4 confers on cells in a model system of metastasis. Basic C-terminal residues enhance the affinity between S100A4 and its best characterized target, a recombinant C-terminal fragment of non-muscle myosin II heavy chain isoform A (NMMHC-IIA). In wild-type S100A4 protein, the presence of the C-terminal lysine, residue 101, enhances the rate of association between S100A4 and NMMHC-IIA. These results identify the amino acids of S100A4 that are involved in metastasis induction and show that the C-terminal region of S100A4 is a possible target for inhibitors of its metastatic action.
钙结合蛋白S100A4可在动物模型系统中诱导转移表型，并且已证明其在各种人类癌症中的表达与转移及患者生存率降低相关。利用一系列嵌套缺失突变体，现已表明，在转移模型系统中，S100A4赋予细胞增强的转移、侵袭和迁移能力需要两个C末端赖氨酸残基。碱性C末端残基增强了S100A4与其特征最明确的靶标——非肌肉肌球蛋白II重链同工型A（NMMHC-IIA）的重组C末端片段之间的亲和力。在野生型S100A4蛋白中，C末端赖氨酸（残基101）的存在提高了S100A4与NMMHC-IIA之间的结合速率。这些结果确定了S100A4中参与转移诱导的氨基酸，并表明S100A4的C末端区域可能是其转移作用抑制剂的靶点。
