Aberrant extra-vascular expression of VE-cadherin (VEC) has been observed in metastasis associated with vasculogenic mimicry (VM); however, the ultimate reason why non-endothelial VEC favors the acquisition of this phenotype is not established. In this study, we show that human malignant melanoma cells have a constitutively high expression of phoshoVEC (pVEC) at Y658; pVEC is a target of focal adhesion kinase (FAK) and forms a complex with p120-catenin and the transcriptional repressor kaiso in the nucleus. FAK inhibition enabled kaiso to suppress the expression of its target genes and enhanced kaiso recruitment to KBS-containing promoters. Finally we have found that ablation of kaiso-repressed genes WNT11 and CCDN1 abolished VM. Thus, identification of pVEC as a component of the kaiso transcriptional complex establishes a molecular paradigm that links FAK-dependent phosphorylation of VEC as a major mechanism by which ectopical VEC expression exerts its function in VM.
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Edited by H. Ichijo.
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This work was supported by Junta de Andalucía, project of Excellence from Junta de Andalucía P10-CTS-0662, P12-CTS-383, Spanish Ministry of Economy and Competitiveness SAF2012-40011-C02-01, SAF2015-70520-R, RTICC RD12/0036/0026, and CIBERONC ISCIII CB16/12/00421.
DD-B performed the experiments, analyzed, interpreted the data, and designed the research; MF-C performed the experiments and analyzed the data; MI-R performed the experiments and interpreted the data; AG-D designed the research, interpreted and analyzed the data; AK interpreted and analyzed the data; FJO designed the research, interpreted and analyzed the data; DD-B, AG-D, and FJO wrote the manuscript.