Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion.
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.
Klucky
Britta
B
Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Mueller
Regina
R
Vogt
Ingeborg
I
Teurich
Sibylle
S
Hartenstein
Bettina
B
Breuhahn
Kai
K
Flechtenmacher
Christa
C
Angel
Peter
P
Hess
Jochen
J
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