Wnt5a诱导ROR1募集皮层肌动蛋白结合蛋白以促进乳腺癌的迁移和转移。
Wnt5a induces ROR1 to recruit cortactin to promote breast-cancer migration and metastasis.
作者信息
Hasan Md Kamrul, Widhopf George F, Zhang Suping, Lam Sharon M, Shen Zhouxin, Briggs Steven P, Parker Barbara A, Kipps Thomas J
机构信息
1Moores Cancer Center, University of California San Diego, La Jolla, CA USA.
Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518060 Guangdong China.
出版信息
NPJ Breast Cancer. 2019 Oct 25;5:35. doi: 10.1038/s41523-019-0131-9. eCollection 2019.
ROR1 is a conserved oncoembryonic surface protein expressed in breast cancer. Here we report that ROR1 associates with cortactin in primary breast-cancer cells or in MCF7 transfected to express ROR1. Wnt5a also induced ROR1-dependent tyrosine phosphorylation of cortactin (Y421), which recruited ARHGEF1 to activate RhoA and promote breast-cancer-cell migration; such effects could be inhibited by cirmtuzumab, a humanized mAb specific for ROR1. Furthermore, treatment of mice bearing breast-cancer xenograft with cirmtuzumab inhibited cortactin phosphorylation in vivo and impaired metastatic development. We established that the proline at 841 of ROR1 was required for it to recruit cortactin and ARHGEF1, activate RhoA, and enhance breast-cancer-cell migration in vitro or development of metastases in vivo. Collectively, these studies demonstrate that the interaction of ROR1 with cortactin plays an important role in breast-cancer-cell migration and metastasis.
ROR1是一种在乳腺癌中表达的保守的癌胚表面蛋白。在此我们报告，在原发性乳腺癌细胞或转染以表达ROR1的MCF7细胞中，ROR1与皮层肌动蛋白结合。Wnt5a还诱导了ROR1依赖的皮层肌动蛋白酪氨酸磷酸化（Y421），该磷酸化募集了ARHGEF1以激活RhoA并促进乳腺癌细胞迁移；这种效应可被cirmtuzumab（一种针对ROR1的人源化单克隆抗体）抑制。此外，用cirmtuzumab治疗携带乳腺癌异种移植瘤的小鼠可在体内抑制皮层肌动蛋白磷酸化并损害转移发展。我们确定，ROR1第841位的脯氨酸是其募集皮层肌动蛋白和ARHGEF1、激活RhoA以及增强体外乳腺癌细胞迁移或体内转移发展所必需的。总的来说，这些研究表明ROR1与皮层肌动蛋白的相互作用在乳腺癌细胞迁移和转移中起重要作用。
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