Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan.
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, 115, Taiwan.
Oncogene. 2019 Oct;38(44):7002-7016. doi: 10.1038/s41388-019-0948-6. Epub 2019 Aug 12.
Cancer cell migration plays a crucial role during the metastatic process. Reversible tyrosine phosphorylation by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) have been implicated in the regulation of cancer cell migration and invasion. However, the underlying mechanisms have not been fully elucidated. Here, we show that depletion of the FERM and PDZ domain-containing protein tyrosine phosphatase PTPN3 enhances lung cancer cell migration/invasion and metastasis by promoting actin filament assembly and focal adhesion dynamics. We further identified Src and DAAM1 (dishevelled associated activator of morphogenesis 1) as interactors of PTPN3. DAAM1 is a formin-like protein involved in the regulation of actin cytoskeletal remodeling. PTPN3 inhibits Src activity and Src-mediated phosphorylation of Tyr652 on DAAM1. The tyrosine phosphorylation of DAAM1 is essential for DAAM1 homodimer formation and actin polymerization. Ectopic expression of a DAAM1 phosphodeficient mutant inhibited F-actin assembly and suppressed lung cancer cell migration and invasion. Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.
癌细胞迁移在转移过程中起着至关重要的作用。蛋白酪氨酸激酶（PTKs）和蛋白酪氨酸磷酸酶（PTPs）的可逆酪氨酸磷酸化被认为参与了癌细胞迁移和侵袭的调节。然而，其潜在的机制尚未完全阐明。在这里，我们发现 FERM 和 PDZ 结构域富含蛋白酪氨酸磷酸酶 PTPN3 的缺失增强了肺癌细胞的迁移/侵袭和转移，促进了肌动蛋白丝组装和焦点黏附动力学。我们进一步鉴定了Src 和 DAAM1（形态发生的离散激活物 1）作为 PTPN3 的相互作用物。DAAM1 是一种参与肌动蛋白细胞骨架重塑调节的formin 样蛋白。PTPN3 抑制 Src 活性和 Src 介导的 DAAM1 上 Tyr652 的磷酸化。DAAM1 的酪氨酸磷酸化对于 DAAM1 同源二聚体的形成和肌动蛋白聚合是必需的。DAAM1 的一个磷酸缺陷突变体的异位表达抑制了 F-肌动蛋白组装，并抑制了肺癌细胞的迁移和侵袭。我们的研究结果揭示了 Src 和 PTPN3 可逆性酪氨酸磷酸化 DAAM1 调节肌动蛋白动力学和肺癌侵袭性的新机制。
