Fig. 4

Dysregulation of ETV5 expression. A Fusion of TMPRSS2 and SLC45A3 with ETV5: the ETV5 gene has thirteen exons and exon 2 is the first coding exon. The breakpoints are located between exons 1 and 2 or exons 7 and 8. The TMPRSS2 gene contains two alternative first exons, 1 and 1a, followed by exons 2–14. Exon 1a is located approximately 1.5 kb downstream of exon (1) The hybrid transcripts yield four mRNAs in which TMPRSS2 sequences are fused to ETV5 exon (2) The SLC45A3 gene contains five exons. The SLC45A3:ETV5 transcript yields an mRNA in which SLC45A3 sequences are fused to ETV5 exon 8. B Crosstalk between ETV5 and molecular signaling pathways: ETV5 is activated through the ERK/MAPK, PI3K/AKT and p38/MAPK signaling pathways initiated by FGFR, GDNF/RET, TrkB and ALK. Activated ETV5 transcriptionally upregulates RET, which translocates to the cell membrane and activates the ERK/MAPK cascade. Phosphorylation of CIC by ERK/MAPK de-represses ETV5 transcription. CIC-DUX4 fusion acts as a transcriptional activator of ETV5. Human endogenous retrovirus-K (HERV-K) Env upregulates ETV5 in an ERK-dependent mechanism. ETV5 is downregulated by miR-8067, miR-219 and miR-200c