title: ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins.
abstract: ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.
authors: Department of Biomedical Sciences and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark. cfr@bric.ku.dk
authors: Camilla
authors: C
authors: Fröhlich
authors: Marie
authors: M
authors: Klitgaard
authors: Julie B
authors: JB
authors: Noer
authors: Alexander
authors: A
authors: Kotzsch
authors: Camilla
authors: C
authors: Nehammer
authors: Pauliina
authors: P
authors: Kronqvist
authors: Jens
authors: J
authors: Berthelsen
authors: Carl
authors: C
authors: Blobel
authors: Marie
authors: M
authors: Kveiborg
authors: Reidar
authors: R
authors: Albrechtsen
authors: Ulla M
authors: UM
authors: Wewer
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis* / Q000737:chemistry* / Q000172:deficiency; D000072199:ADAM12 Protein; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000737:chemistry* / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human