A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis.
A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis.
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DOI：
10.1038/ncb3464
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发表时间：
2017-02
影响因子：
21.3
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Li C;Wang S;Xing Z;Lin A;Liang K;Song J;Hu Q;Yao J;Chen Z;Park PK;Hawke DH;Zhou J;Zhou Y;Zhang S;Liang H;Hung MC;Gallick GE;Han L;Lin C;Yang L
骨转移仍然是一个严重的健康问题，因为有限的治疗选择。在这里，我们报告说，ROR 1-HER 3和Hippo-YAP通路之间的串扰促进乳腺癌骨转移在一个长期的非编码RNA依赖的方式。从机制上讲，孤儿受体酪氨酸激酶ROR 1磷酸化HER 3在一个以前未鉴定的网站Tyr 1307，神经调节蛋白刺激后，独立于其他ErbB家族成员。p-HER 3 Tyr 1307募集LLGL 2-MAYA-NSUN 6 RNA-蛋白质复合物以在Lys 59处甲基化Hippo/MST 1。这种甲基化导致肿瘤细胞中MST 1失活和雅普靶基因的激活，从而促进破骨细胞分化和骨转移。此外，ROR 1、p-HER 3 Tyr 1307和MAYA水平升高与肿瘤转移和不良结局相关。我们的数据提供了对ROR 1-HER 3和Hippo-YAP通路在癌症特异性背景下的机制调节和联系的见解，也暗示了骨转移和可能的耐药肿瘤的有价值的治疗靶点。
Bone metastases remain as a serious health concern because of limited therapeutic options. Here, we report that crosstalk between ROR1-HER3 and the Hippo-YAP pathway promotes breast cancer bone metastasis in a long noncoding RNA-dependent fashion. Mechanistically, the orphan receptor tyrosine kinase ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307, upon neuregulin stimulation, independently of other ErbB family members. p-HER3 Tyr1307 recruits the LLGL2-MAYA-NSUN6 RNA-protein complex to methylate Hippo/MST1 at Lys59. This methylation leads to MST1 inactivation and activation of YAP target genes in tumor cells, which elicits osteoclast differentiation and bone metastasis. Furthermore, increased ROR1, p-HER3 Tyr1307 and MAYA levels correlate with tumor metastasis and unfavorable outcomes. Our data provide insights into the mechanistic regulation and linkage of the ROR1-HER3 and Hippo-YAP pathway in cancer-specific context, and also imply valuable therapeutic targets for bone metastasis and possible therapy-resistant tumors.