BioProject

Prss14/ST14 is a type II transmembrane serine protease which is reported to be overexpressed in many epithelial cancers and plays critical roles in cancer initiation, progression, and metastasis. More...

Prss14/ST14 is a type II transmembrane serine protease which is reported to be overexpressed in many epithelial cancers and plays critical roles in cancer initiation, progression, and metastasis. Prss14/ST14 undergoes ectodomain shedding in response to various stimulus including serum, TGF-β, and PMA. The fate of the residual membrane anchored N-terminal fragment (NTF) remains unknown. We show that the membrane-bound remnant, which is resulted from PMA-induced ectodomain shedding mediated by tumor necrosis factor-a converting enzyme (TACE) is subjected to regulated intramembrane proteolysis (RIP). The signal peptide peptidase-like 2b (SPPL2b) is identified as the enzyme carrying out this RIP. After RIP, we demonstrate that the generated soluble Prss14/ST14 intracellular domain (EICD) translocates to the nucleus. The ability of cell invasion and migration is abolished in SPPL2b-knockdown cells and these are recovered by transfection of exogenous EICD (N55). Furthermore, EICD is able to activate transcription and this observation prompts us to investigate target genes of EICD using RNA-seq. Analysis of RNA-seq results using samples from multiple conditions and network analysis reveal the EICD target genes that are associated with migration, invasion, and EMT. Furthermore, N55-overexpressing cell lines show scattered phenotype and increased EMT markers expression. ER-negative breast cancer patients with high expression of FOS or MMP13, the target genes, and Prss14/ST14 show poor survival outcomes, suggesting these genes can be used for prognosis markers of ER negative breast cancer. In this study, we propose a new mechanism to facilitate the cancer cell migration, invasion, and EMT by transcriptional regulation of EICD generated by SPPL2b. Overall design: We performed RNA-seq of mouse thymoma cell lines, 427.1.86 cells from 6 conditions to identify the target genes of EICD using Illumina HiSeq 2500. We tested the effect of EICD on transcriptional regulation in cells with increased EICD by PMA-induced shedding and transfection of exogenous EICD and with decreased EICD by knockdown of SPPL2b. Less...