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Li, Chunlai; Wang, Shouyu; Xing, Zhen; Lin, Aifu; Liang, Ke; Song, Jian; Hu, Qingsong; Yao, Jun; Chen, Zhongyuan; Park, Peter K; Hawke, David H; Zhou, Jianwei; Zhou, Yan; Zhang, Shuxing; Liang, Han; Hung, Mien-Chie; Gallick, Gary E; Han, Leng; Lin, Chunru; Yang, Liuqing
Nature cell biology, 02/2017, Letnik: 19, Številka: 2Journal Article
Bone metastases remain 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, following 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 tumour cells, which elicits osteoclast differentiation and bone metastasis. Furthermore, increased ROR1, p-HER3 Tyr1307 and MAYA levels correlate with tumour metastasis and unfavourable outcomes. Our data provide insights into the mechanistic regulation and linkage of the ROR1-HER3 and Hippo-YAP pathway in a cancer-specific context, and also imply valuable therapeutic targets for bone metastasis and possible therapy-resistant tumours.
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in: SICRIS
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