Regulation of Endothelial Tie2 Signaling by a Extracellular Protease, Epithin/ PRSS14

초록

Epithin (also known as Matriptase, Prss14, ST14, or MT-SP1), a type II transmembrane serine protease, is involved in normal epithelial development and tumor progression. Here we report, as an interacting substrate of epithin, a receptor tyrosine kinase Tie2 that is known for its roles in the vessel stability. Epithin interacts with and degrades the Tie2 extracellular portion that contains the ligand angiopoietin binding domain. Epithin is located in the neighbor of Tie2 expressing vessels in normal tissue. Furthermore, epithin can cleave and degrade Tie2 not only in the same cell but also from neighboring cells nearby, resulting in the degradation of the Tie2 ectodomain. The remaining Tie2 fragment was highly tyr-phosphorylated and was able to recruit a downstream effector, phosphatidylinositol 3-kinase. Knocking down epithin expression using short hairpin RNA in thymic epithelial tumor cells reduced the migration through endothelial cells that show the actin rearrangement during the process. Therefore, we propose that epithin, which regulates endothelial Tie2 functions, plays a critical role in the fine tuning of transendothelial migration for normal and cancer cells. Tumor cell seeding assay is in progress to test the transendothelial function of epithelial tumor lines.