title: ADAM15 modulates outside-in signalling in  chondrocyte-matrix interactions.
abstract: ADAM15 belongs to a family of transmembrane multi-domain proteins implicated in proteolysis, cell-cell and cell-matrix interactions in various disease conditions. In osteoarthritis (OA), ADAM15 is up-regulated in the chondrocytes already at early stages of cartilage degeneration where it seems to exert homeostatic effects likely associated with its ability to enhance integrin-mediated chondrocyte adhesion to the surrounding collagen matrix. The aim of our present study was, therefore, to characterize functional domains of ADAM15 involved in collagen II (CII) interaction and to analyse associated outside-in signalling events. Accordingly, ADAM15 and respective deletion mutants were stably transfected into the chondrocyte cell line T/C28a4. Transfected cells were adhered to CII and phosphoproteins analysed by Western blotting. Co-immunoprecipitation served to identify protein binding to ADAM15. Our results elucidate the prodomain as critical for the capacity of ADAM15 to enhance CII adhesion, thereby identifying for the first time a cell-adhesive role of a metalloproteinase prodomain. Moreover, the cytoplasmic tail of ADAM15 confers a modulatory effect on the autophosphorylation site Y397 of the focal adhesion kinase (FAK) during chondrocyte-collagen interaction. In conclusion, the newly uncovered impact of ADAM15 on signalling events that arise from chondrocyte interactions with its collagen matrix might contribute to the elucidation of the mechanism underlying its proposed chondroprotective role in degenerative cartilage disease.
authors.affiliation: Division of Rheumatology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Beate B
authors.initials: BB
authors.lastname: Böhm
authors.affiliation: Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schirner
authors.affiliation: Division of Rheumatology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Burkhardt
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D017931:DNA Primers; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; D051722:ADAM Proteins; C098660:ADAM15 protein, human
references.citation: Biol Chem. 2005 Sep;386(9):845-55
references.pmid: 16164409
references.citation: Cancer Sci. 2007 May;98(5):621-8
references.pmid: 17355265
references.citation: Genes Dev. 2003 Jan 1;17(1):7-30
references.pmid: 12514095
references.citation: J Clin Invest. 1994 Dec;94(6):2307-16
references.pmid: 7989586
references.citation: Nat Rev Mol Cell Biol. 2005 Jan;6(1):32-43
references.pmid: 15688065
references.citation: J Cell Sci. 2003 Apr 15;116(Pt 8):1409-16
references.pmid: 12640026
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):5857-64
references.pmid: 9600884
references.citation: J Biol Chem. 2002 May 17;277(20):17804-10
references.pmid: 11882657
references.citation: J Biol Chem. 1999 May 7;274(19):13427-33
references.pmid: 10224107
references.citation: J Biol Chem. 2007 Dec 7;282(49):35712-21
references.pmid: 17895248
references.citation: Arthritis Rheum. 2005 Apr;52(4):1100-9
references.pmid: 15818704
references.citation: Biochim Biophys Acta. 2004 Jul 5;1692(2-3):103-19
references.pmid: 15246682
references.citation: Curr Opin Cell Biol. 2003 Oct;15(5):598-606
references.pmid: 14519395
references.citation: FASEB J. 2001 Aug;15(10):1837-9
references.pmid: 11481247
references.citation: Arthritis Rheum. 2006 May;54(5):1357-60
references.pmid: 16645963
references.citation: J Biol Chem. 1999 Oct 22;274(43):30563-70
references.pmid: 10521439
references.citation: J Biol Chem. 2002 Sep 13;277(37):33683-9
references.pmid: 12091380
references.citation: Ann Biomed Eng. 2004 Mar;32(3):435-46
references.pmid: 15095818
references.citation: Arthritis Rheum. 2001 Sep;44(9):2046-54
references.pmid: 11592366
references.citation: Arthritis Rheum. 1999 Sep;42(9):1946-50
references.pmid: 10513811
references.citation: J Cell Sci. 1999 Feb;112 ( Pt 4):579-87
references.pmid: 9914169
references.citation: Mol Cell Biol. 1995 Feb;15(2):954-63
references.pmid: 7529876
references.citation: FASEB J. 1997 Feb;11(2):173-80
references.pmid: 9039960
references.citation: J Biol Chem. 2002 Feb 15;277(7):4999-5007
references.pmid: 11741929
references.citation: Birth Defects Res C Embryo Today. 2006 Mar;78(1):24-46
references.pmid: 16622847
references.citation: J Biol Chem. 1999 Oct 29;274(44):31693-9
references.pmid: 10531379
references.citation: J Biol Chem. 1992 Nov 25;267(33):23439-42
references.pmid: 1429685
references.citation: Trends Biochem Sci. 2005 Jul;30(7):413-22
references.pmid: 15949939
references.citation: Arthritis Rheum. 2005 Jan;52(1):136-43
references.pmid: 15641077