The Cysteine-Rich Domain of Human Adam 12 Supports Cell Adhesion through Syndecans and Triggers Signaling Events That Lead to β1 Integrin–Dependent Cell Spreading
By K. Iba, R. Albrechtsen, B. Gilpin, Camilla Fröhlich, F. Loechel, A. Zolkiewska, K. Ishiguro, T. Kojima, Wei Liu, J. Langford and 4 more. 2000
273 citations recorded by the source corpus.
The ADAMs (a disintegrin and metalloprotease) family of proteins is involved in a variety of cellular interactions, including cell adhesion and ecto- domain shedding. Here we show that ADAM 12 binds to cell surface syndecans. Three forms of recombinant ADAM 12 were used in these experiments: the cys-teine-rich domain made in Escherichia coli (rADAM 12-cys), the disintegrin-like and cysteine-rich domain made in insect cells (rADAM 12-DC), and full-length human ADAM 12-S tagged with green fluorescent protein made in mammalian cells (rADAM 12-GFP). Mesenchymal cells specifically and in a dose-dependent manner attach to ADAM 12 via members of the syndecan family. After binding to syndecans, mesenchymal cells spread and form focal adhesions and actin stress fibers. Integrin β1 was responsible for cell spreading because function-blocking monoclonal antibodies completely inhibited cell spreading, and chondroblasts lacking β1 integrin attached but did not spread. These data suggest that mesenchymal cells use syndecans as the initial receptor for the ADAM 12 cysteine-rich domain–mediated cell adhesion, and then the β1 integrin to induce cell spreading. Interestingly, carcinoma cells attached but did not spread on ADAM 12. However, spreading could be efficiently induced by the addition of either 1 mM Mn2+ or the β1 integrin–activating monoclonal antibody 12G10, suggesting that in these carcinoma cells, the ADAM 12–syndecan complex fails to modulate the function of β1 integrin.
Subfields: Cell Biology, Immunology and Allergy, Oncology
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Citations in the corpus
- The ADAMs family of metalloproteases: multidomain proteins with multiple functions. (2003, background): “…in a study showing that the cysteinerich domain of ADAM12 supports the in vitro binding of several different tumor cell lines, as well as a variety of nontumorigenic cells of bone and muscle origin, through the interaction with cell surface heparan-sulfate proteoglycans (Iba et al. 1999, 2000).”
- The cysteine-rich domain regulates ADAM protease function in vivo (2002, background): “The Rockefeller University Press, 0021-9525/2002/12/893/10 $5.00 The Journal of Cell Biology, Volume 159, Number 5, December 9, 2002 893–902 http://www.jcb.org/cgi/doi/10.1083/jcb.200206023 JCB Article 893”
- Potential Role for ADAM15 in Pathological Neovascularization in Mice (2003, background): “ADAMs are also thought to have roles in cell-cell adhesion, for example, through interactions with integrins (9, 18, 49) or syndecans ( 32 , 71).”
- The ADAM metalloproteinases (2008, background): “For ADAM-12, the Cys-rich domain mediates adhesive interactions with syndecans, leading subsequently to engagement with b1-containing integrins (Iba et al., 2000; Thodeti et al., 2003).”
- Physiology and pathophysiology of matrix metalloproteases (2010, background): “MMPs thus contribute to the generation of protein species with vastly differing activities from a single, original gene product.”
- Syndecan-1 regulates αvβ5 integrin activity in B82L fibroblasts (2006, background): “…mechanism, mesenchymal cells bind the disintegrin domain of ADAM-12 via 1 integrins and interact with the cysteine-rich domain of ADAM-12 via Sdc4 (Iba et al., 2000); cells that overexpress Sdc4 display increased levels of activated 1 integrin (Thodeti et al., 2003), an activity that requires the…”
- Phenotypic Analysis of Meltrin α (ADAM12)-Deficient Mice: Involvement of Meltrin α in Adipogenesis and Myogenesis (2003, background): “Other studies suggest that ADAMs are also involved in cell-cell or cell-extracellular matrix interactions through their interaction with integrins (6, 10, 27, 48) or proteoglycans ( 15 ).”