Epithin intracellular domain (EICD), generated through the regulated intramembrane proteolysis, acts as a transcriptional regulator

초록

Epithin intracellular domain (EICD), generated through the regulated intramembrane proteolysis, acts as a transcriptional regulator Sangbum Kim, Hyo Seon Lee, Moon Gyo Kim*, and Dongeun Park School of Biological Sciences, Seoul National University, Seoul, Republic of Korea, 151-747 *Department of Biological Sciences, Inha University, Incheon, Republic of Korea, 402-751 Epithin (matriptase in human) is a type II transmembrane serine protease (TTSP) that is widely expressed in epithelial cells. Overexpression of epithin has been found in the multiple carcinomas, and up-regulation of epithin correlated well with cancer growth and metastasis. Although several studies have reported roles of the epithin extracellular domains, which contains the serine protease activity, in cancer growth and metastasis, roles of the epithin intracellular domain have not been reported yet. Here, we report that generation of the epithin intracellular domain fragment (EICD) by the regulated intramembrane proteolysis, and demonstrate that EICD is liberated from the plasma membrane and translocates to the nucleus after epithin ectodomain shedding. It was also found that the nuclear EICD activates the expression of proteins that are implicated in cancer growth and metastasis, such as epithin itself and MMP-2. The activity of EICD as a transcriptional modulator required SP1-binding elements in the promoter region of the genes. Moreover, overexpression of EICD in epithelial cells induced the expression of epithin and MMP-2, and also the cells exhibited the elevated invasion activity. Based on these findings, we suggest that EICD generated by proteolytic process acts as a transcriptional modulator and as an inducer of cancer progression through controlling epithin and/or MMP-2 expression.