1. A ROR1–HER3–lncRNA signalling axis modulates the Hippo–YAP pathway to regulate bone metastasis
- Author
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Shouyu Wang, David H. Hawke, Aifu Lin, Gary E. Gallick, Leng Han, Ke Liang, Liuqing Yang, Zhen Xing, Han Liang, Yan Zhou, Jianwei Zhou, Chunru Lin, Qingsong Hu, Jun Yao, Peter K. Park, Zhongyuan Chen, Shuxing Zhang, Jian Song, Chunlai Li, and Mien Chie Hung
- Subjects
0301 basic medicine ,MST1 ,Locked nucleic acid ,Receptor, ErbB-3 ,Orphan receptor tyrosine kinase ,Bone Neoplasms ,Protein Serine-Threonine Kinases ,Receptor Tyrosine Kinase-like Orphan Receptors ,Article ,Receptor tyrosine kinase ,03 medical and health sciences ,Breast cancer ,MAYA ,Hippo-YAP pathway ,Non-histone protein methylation ,Osteoclast ,Cell Line, Tumor ,medicine ,Humans ,Hippo Signaling Pathway ,long noncoding RNA ,skin and connective tissue diseases ,ROR1 ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Hippo signaling pathway ,biology ,Kinase ,CTGF ,Bone metastasis ,YAP-Signaling Proteins ,Cell Biology ,Phosphoproteins ,medicine.disease ,3. Good health ,Cell biology ,body regions ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,RNA, Long Noncoding ,Signal transduction ,Signal Transduction ,Transcription Factors - Abstract
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.
- Published
- 2017