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

Nat Cell Biol. 2017 Feb;19(2):106-119. doi: 10.1038/ncb3464. Epub 2017 Jan 23.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / secondary
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Hippo Signaling Pathway
  • Humans
  • Phosphoproteins / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Long Noncoding / metabolism
  • Receptor Tyrosine Kinase-like Orphan Receptors / metabolism*
  • Receptor, ErbB-3 / metabolism*
  • Signal Transduction*
  • Transcription Factors
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • RNA, Long Noncoding
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • ERBB3 protein, human
  • ROR1 protein, human
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Receptor, ErbB-3
  • Protein Serine-Threonine Kinases