Chen Y-R, Chou H-C, Yang C-H, Chen H-Y, Liu Y-W, Lin T-Y, Yeh C-L, Chao W-T, Tsou H-H, Chuang H-C, Tan T-H
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Department of Life Science, Tunghai University, Taichung, Taiwan.
Oncogene. 2017 Nov 23;36(47):6509-6517. doi: 10.1038/onc.2017.255. Epub 2017 Jul 31.
Vaccinia H1-related phosphatase (VHR/DUSP3) is a member of the dual-specificity phosphatase family. Deregulation of VHR is observed in various malignant diseases. We identified focal adhesion kinase (FAK) as a VHR-interacting molecule. Over-expression of VHR decreased tyrosine phosphorylation of FAK and decreasing VHR promoted FAK tyrosine phosphorylation. In vitro assays proved that recombinant VHR directly dephosphorylated FAK and paxillin. VHR-knockout mice did not have obvious abnormality; however, VHR-knockout cells showed decreased expression of integrins and FAK but stronger FAK and paxillin phosphorylation upon attachment to fibronectin. Additionally, VHR-knockout fibroblast and lung epithelial cells had elevated ligand-induced epidermal growth factor receptor (EGFR) phosphorylation. Inducible expression of VHR suppressed directional cell migration, and VHR deficiency resulted in a higher cell migratory ability. VHR-knockout cells have stronger FAK phosphorylation in cell adhesions, long-lasting trailing ends and slower turnover of focal adhesions. These collective data indicate that VHR is a FAK phosphatase and participates in regulating the formation and disassembly of focal adhesions.
痘苗H1相关磷酸酶（VHR/DUSP3）是双特异性磷酸酶家族的成员。在各种恶性疾病中均观察到VHR的失调。我们鉴定出粘着斑激酶（FAK）是一种与VHR相互作用的分子。VHR的过表达降低了FAK的酪氨酸磷酸化，而VHR的减少则促进了FAK的酪氨酸磷酸化。体外实验证明，重组VHR可直接使FAK和桩蛋白去磷酸化。VHR基因敲除小鼠没有明显异常；然而，VHR基因敲除细胞在附着于纤连蛋白时，整合素和FAK的表达降低，但FAK和桩蛋白的磷酸化增强。此外，VHR基因敲除的成纤维细胞和肺上皮细胞的配体诱导的表皮生长因子受体（EGFR）磷酸化升高。VHR的诱导表达抑制细胞定向迁移，而VHR缺陷导致更高的细胞迁移能力。VHR基因敲除细胞在细胞黏附、持久的尾端以及粘着斑周转较慢时具有更强的FAK磷酸化。这些综合数据表明，VHR是一种FAK磷酸酶，并参与调节粘着斑的形成和分解。
