title: Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion.
abstract: Recently, we described phorbol ester-induced expression of the brain and skin serine proteinase Bssp/kallikrein 6 (Klk6), the mouse orthologue of human KLK6, in mouse back skin and in advanced tumor stages of a well-established multistage tumor model. Here, we show KLK6 up-regulation in squamous skin tumors of human patients and in tumors of other epithelial tissues. Ectopic Klk6 expression in mouse keratinocyte cell lines induces a spindle-like morphology associated with accelerated proliferation, migration, and invasion capacity. We found reduced E-cadherin protein levels in the cell membrane and nuclear translocation of beta-catenin in Klk6-expressing mouse keratinocytes and human HEK293 cells transfected with a KLK6 expression plasmid. Additionally, HEK293 cells exhibited induced T-cell factor-dependent transcription and impaired cell-cell adhesion in the presence of KLK6, which was accompanied by induced E-cadherin ectodomain shedding. Interestingly, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 interfere with KLK6-induced E-cadherin ectodomain shedding and rescue the cell-cell adhesion defect in vitro, suggesting the involvement of matrix metalloproteinase and/or a disintegrin and metalloproteinase (ADAM) proteolytic activity. In line with this assumption, we found increased levels of the mature 62-kDa ADAM10 proteinase in cells expressing ectopic KLK6 compared with mock controls. Finally, enhanced epidermal keratinocyte proliferation and migration in concert with decreased E-cadherin protein levels are confirmed in an in vivo Klk6 transgenic mouse model.
authors.affiliation: Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Klucky
authors.forename: Regina
authors.initials: R
authors.lastname: Mueller
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Vogt
authors.forename: Sibylle
authors.initials: S
authors.lastname: Teurich
authors.forename: Bettina
authors.initials: B
authors.lastname: Hartenstein
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
mesh_terms: D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002450:Cell Communication / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism