title: Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration.
abstract: Epithin/PRSS14, 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 well known for important roles in the vessel stability. Epithin interacts with and degrades the Tie2 extracellular portion that contains the ligand-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 phosphorylated and was able to recruit a downstream effector, phosphatidylinositol 3-kinase. Knocking down epithin expression using short hairpin RNA in thymoma cell severely impaired the migration through endothelial cells that show the actin rearrangement during the process. The diminution of epithin protein expression in 4T1 breast cancer cells caused the significant decrease in the number of transendothelial migrating cells in vitro as well as in those of metastasizing tumor nodules in vivo, 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.
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Chungho
authors.initials: C
authors.lastname: Kim
authors.forename: Hyo Seon
authors.initials: HS
authors.lastname: Lee
authors.forename: Deokjae
authors.initials: D
authors.lastname: Lee
authors.forename: Sang Don
authors.initials: SD
authors.lastname: Lee
authors.forename: Eun-Gyung
authors.initials: EG
authors.lastname: Cho
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Yang
authors.forename: Sang Bum
authors.initials: SB
authors.lastname: Kim
authors.forename: Dongeun
authors.initials: D
authors.lastname: Park
authors.forename: Moon Gyo
authors.initials: MG
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D042787:Receptor, TIE-2 / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D017077:Culture Media, Conditioned; D042787:Receptor, TIE-2; D012697:Serine Endopeptidases; C485596:ST14 protein, human; D013755:Tetradecanoylphorbol Acetate