Epithin/Prss14 intracellular domain realeased by the regulated intramenrbane proteolysis is a transcriptional regulator of cell migration and invasion

초록

We previously showed that soluble form of PRSS14/Epithin is released from the membrane and plays role in angiogenesis. We also showed phorbol myristate acetate (PMA) and TGF? increase PRSS14/Epithin. Here, we show JNK inhibitor, SP600125, and/or PMA can induce PRSS14/Epithin shedding through the PKCBII and TACE pathway. The shedding induced by SP600125 was inhibited by the treatment of anisomycin, an upstream activator of JNKs, and also by the treatment of conventional PKC inhibitors (Go6976 and PKCβ selective inhibitor). Knockdown of PKCβ, but not PKCα significantly inhibited PMA and SP600125 induced PRSS14/Epithin shedding. Overexpression of dominant negative (dn) PKCβII effectively inhibited PRSS14/Epithin shedding induced by PMA and SP600125. In addition, SP600125 increased the PKCβII phosphorylation at Ser660 and its membrane translocation. SP600125 also caused the increase of PKCβII activity in 427.1.86 cells. Treatment of PKCβ selective inhibitor reduced the basal level of PRSS14/Epithin shedding in more than two mouse and human cancer cell lines. Both the inhibition of TACE with TAPI-0 and the knockdown of TACE expression with siRNA reduced PMA and/or SP600125 induced PRSS14/Epithin shedding, suggesting shedding is mediated by TACE. PKCBII specific knock down in 427.1.86 cell lost PMA and/or SP600125 induced cell invasion, suggesting that PKCBII is critical for Prss14/epithin shedding as well as its cellular function. Analyses of TCGA breast cancer revealed that ER negative patients, showing high ST14 expression related poor survival, express higher PKCBII and TACE expression, while lower JNK2 and JNK3 expression, than ER positive patients. Through these results, we propose that caution should be made in the treatment of breast cancer patients with JNK related therapy trials.