Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion

摘要: Tumor progression to invasive carcinoma is associated with activation of SRC family kinase (SRC, YES, FYN) activity and loss cellular cohesion. The hippo pathway-regulated cofactor YAP1 supports the tumorigenicity RAS mutations but requires both inactivation signaling YES-mediated phosphorylation for oncogenic activity. Exactly how kinases are activated lost in sporadic human malignancies remains unknown. Here, we provide evidence that hippo-mediated inhibition upon promoter methylation effector scaffold RASSF1A. We find RASSF1A reduces YAP phospho-S127, which derepresses YAP1, actively by switching RASSF1 transcription independently transcribed RASSF1C isoform promotes Tyr Using affinity proteomics, proximity ligation, real-time molecular visualization, targets SRC/YES epithelial cell-cell junctions tyrosine E-cadherin, β-catenin, YAP1. restricts activity, preventing motility, invasion, tumorigenesis in vitro in vivo, epigenetic correlating increased inhibitory pY527-SRC breast tumors. These data imply distinct isoforms have opposing functions, a biomarker explain correlations advanced disease humans. ablation integrity together subsequent nuclear localization allows transcriptional β-catenin/TBX-YAP/TEAD target genes, including Myc, an phenotype. findings define gene transcript as tumor suppressor mechanism under control.