EWI-2 regulates melanoma growth and lung metastasis in a TGF-1-dependent manner

EWI-2 (IgSF8) plays a novel, bifunctional role in melanoma cells. EWI-2 inhibits migration, metastasis, EMT-like changes, and CD271-dependent invasion in multiple melanoma cell lines. On the other hand, EWI-2 supports melanoma cell proliferation, survival, and xenograft growth. Consistent with these results, EWI-2 levels were elevated in human malignant melanoma, but not in metastatic melanoma samples. Altered melanoma cell functions, caused by EWI-2 ablation, are almost entirely dependent on enhanced TRF-1 signaling, and also require contributions from tetraspanin proteins CD9 and CD81. In melanoma cells lacking EWI-2, tetraspanins CD9 and CD81 enhance TRF-1 signaling by facilitating TR-2TR-1 receptor complex formation. When EWI-2 is present, CD9 and CD81 are diverted into EWI-2 complexes, and thus TRF-1 signaling is inhibited.

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