CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling.
CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling.
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CD147 通过与膜联蛋白 A2 和 DOCK3-β-连环蛋白-WAVE2 信号传导直接相互作用来调节癌症迁移
DOI：
10.18632/oncotarget.6723
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发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Jiang JL
中科院分区：
文献类型：
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作者：
Cui HY;Wang SJ;Miao JY;Fu ZG;Feng F;Wu J;Yang XM;Chen ZN;Jiang JL
不适当迁移特征的获得是肿瘤转移的关键。已有研究表明CD147和Annexin A2参与了肿瘤细胞运动的调控，但调控机制尚不清楚。在这项研究中，我们证明了CD147与Annexin A2的n端结构域物理相互作用，并降低了Annexin A2在酪氨酸23上的磷酸化。体外激酶实验表明，CD147的I结构域对于CD147介导的Src对Annexin A2磷酸化的下调是必不可少的。此外，我们发现p-Annexin A2促进了细胞分裂奉献子3 （DOCK3）的表达，DOCK3阻断了β-catenin的核易位，从而抑制了β-catenin的信号传导。此外，DOCK3抑制板层基动力学和肿瘤细胞运动。此外，我们发现β-catenin信号通路增加了WAVE2的表达。因此，DOCK3通过抑制β-catenin信号传导而成为WAVE2表达的负调控因子。我们的研究首次证明CD147通过与Annexin A2和DOCK3-β-catenin-WAVE2信号轴的直接相互作用促进肿瘤细胞的运动和转移。
The acquisition of inappropriate migratory feature is crucial for tumor metastasis. It has been suggested that CD147 and Annexin A2 are involved in regulating tumor cell movement, while the regulatory mechanisms are far from clear. In this study, we demonstrated that CD147 physically interacted with the N-terminal domain of Annexin A2 and decreased Annexin A2 phosphorylation on tyrosine 23. In vitro kinase assay showed that the I domain of CD147 was indispensable for CD147-mediated downregulation of Annexin A2 phosphorylation by Src. Furthermore, we determined that p-Annexin A2 promoted the expression of dedicator of cytokinesis 3 (DOCK3) and DOCK3 blocked β-catenin nuclear translocation, resulting in inhibition of β-catenin signaling. In addition, DOCK3 inhibited lamellipodium dynamics and tumor cell movement. Also, we found that β-catenin signaling increased WAVE2 expression. Therefore, DOCK3 was characterized as a negative regulator of WAVE2 expression via inhibiting β-catenin signaling. Our study provides the first evidence that CD147 promotes tumor cell movement and metastasis via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling axis.