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.

Genome-wide association studies have identified and repeatedly confirmed the association of rs3197999 in MST1 with inflammatory bowel disease (IBD). However, the underlying pathophysiology remains unclear. rs3197999 is a non-synonymous single-nucleotide polymorphism which modifies the function of macrophage stimulating protein-1 (MST1). We show by haplotyping that rs3197999 is in linkage disequilibrium with rs1050450 in GPX1, with almost complete cosegregation of the minor alleles. As shown by immunoassay, rs3197999 influences the MST-1 level in serum. But also rs1050450 causes an amino acid exchange in glutathione peroxidase 1 (GPx-1) and reduced activity of this antioxidant enzyme. The association of GPx deficiency and IBD in mice was already shown. We propose that GPx-1 is a better candidate than MST1 for the pathophysiologic link between IBD locus 12 and IBD.