title: Ror2-Src signaling in metastasis of mouse melanoma cells is inhibited by NRAGE.
abstract: The receptor tyrosine kinase (RTK) Ror2 plays important roles in developmental morphogenesis and mediates the filopodia formation in Wnt5a-induced cell migration. However, the function of Ror2 in noncanonical Wnt signaling resulting in cancer metastasis is largely unknown. Here, we show that Ror2 expression is higher in the highly metastatic murine B16-BL6 melanoma cells than in the low metastatic variant B16 cells. Overexpression of Ror2 increases the metastasis ability of B16 cells, and knockdown of Ror2 reduces the migration ability of B16-BL6 cells. Furthermore, the inhibition of Src kinase activity is critical for the Ror2-mediated cell migration upon Wnt5a treatment. The C-terminus of Ror2, which is deleted in brachydactyly type B (BDB), is essential for the mutual interaction with the SH1 domain of Src. Intriguingly, the Neurotrophin receptor-interacting MAGE homologue (NRAGE), which, as we previously reported, can remodel the cellular skeleton and inhibit cell-cell adhesion and metastasis of melanoma and pancreatic cancer, sharply blocks the interaction between Src and Ror2 and inhibits Ror2-mediated B16 cell migration by decreasing the activity of Src and focal adhesion kinase (FAK). Our data show that Ror2 is a potential factor in the tumorigenesis and metastasis in a Src-dependent manner that is negatively regulated by NRAGE.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, and Medical School of Nanjing University, Nanjing, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Lai
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Chao-Shun
authors.initials: CS
authors.lastname: Chu
authors.forename: Jia-Yin
authors.initials: JY
authors.lastname: Hao
authors.forename: Chuan-Jun
authors.initials: CJ
authors.lastname: Wen
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C486541:Maged1 protein, mouse; D009363:Neoplasm Proteins; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases