A ROR1–HER3–lncRNA signalling axis modulates the Hippo–YAP pathway to regulate bone metastasis
Nature cell biology, 2017•nature.com
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 …
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 …
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.
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