A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis

Chunlai Li; Shouyu Wang; Zhen Xing; Aifu Lin; Ke Liang; Jian Song; Qingsong Hu; Jun Yao; Zhongyuan Chen; Peter K. Park; David H. Hawke; Jianwei Zhou; Yan Zhou; Shuxing Zhang; Han Liang; Mien Chie Hung; Gary E. Gallick; Leng Han; Chunru Lin; Liuqing Yang

doi:10.1038/ncb3464

A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis

Chunlai Li, Shouyu Wang, Zhen Xing, Aifu Lin, Ke Liang, Jian Song, Qingsong Hu, Jun Yao, Zhongyuan Chen, Peter K. Park, David H. Hawke, Jianwei Zhou, Yan Zhou, Shuxing Zhang, Han Liang, Mien Chie Hung, Gary E. Gallick, Leng Han, Chunru Lin, Liuqing Yang

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233 Scopus citations

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.

Original language	English (US)
Pages (from-to)	106-119
Number of pages	14
Journal	Nature cell biology
Volume	19
Issue number	2
DOIs	https://doi.org/10.1038/ncb3464
State	Published - Jan 31 2017

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Cell Biology

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10.1038/ncb3464

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Li, C., Wang, S., Xing, Z., Lin, A., Liang, K., Song, J., Hu, Q., Yao, J., Chen, Z., Park, P. K., Hawke, D. H., Zhou, J., Zhou, Y., Zhang, S., Liang, H., Hung, M. C., Gallick, G. E., Han, L., Lin, C., & Yang, L. (2017). A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis. Nature cell biology, 19(2), 106-119. https://doi.org/10.1038/ncb3464

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title = "A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis",

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.",

author = "Chunlai Li and Shouyu Wang and Zhen Xing and Aifu Lin and Ke Liang and Jian Song and Qingsong Hu and Jun Yao and Zhongyuan Chen and Park, {Peter K.} and Hawke, {David H.} and Jianwei Zhou and Yan Zhou and Shuxing Zhang and Han Liang and Hung, {Mien Chie} and Gallick, {Gary E.} and Leng Han and Chunru Lin and Liuqing Yang",

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AU - Song, Jian

AU - Hu, Qingsong

AU - Yao, Jun

AU - Chen, Zhongyuan

AU - Park, Peter K.

AU - Hawke, David H.

AU - Zhou, Jianwei

AU - Zhou, Yan

AU - Zhang, Shuxing

AU - Liang, Han

AU - Hung, Mien Chie

AU - Gallick, Gary E.

AU - Han, Leng

AU - Lin, Chunru

AU - Yang, Liuqing

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N2 - 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.

AB - 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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A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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