Rabbit synovial fibroblasts (RSF) express basal levels of the metalloproteinases (MMP) collagenase, stromelysin-1 and 92-kD gelatinase when plated on intact fibronectin (FN), but elevated levels when plated on either the central RGD-containing cell-binding region of FN (120FN) or antibody against the alpha 5 beta 1 integrin, suggesting that domains outside 120FN may suppress the induction of MMP (Werb, Z., P. M. Tremble, O. Behrendtsen, E. Crowley, and C.H. Damsky. 1989. J. Cell Biol. 109:877-889). We therefore attempted to reconstitute the basal signaling of intact FN by plating RSF on 120FN together with domains of FN outside this region. Large COOH-terminal fragments containing both the heparin-binding and HICS domains suppressed MMP when combined with 120FN. To map the active sequences, peptides from this region and larger fragments that did, or did not, include the CS-1 portion of IIICS were tested. Only CS-1 peptide, or larger fragments containing CS-1, suppressed MMP expression induced by 120FN. In contrast, peptide V from the heparin-binding region, shown previously to stimulate focal contact formation, further enhanced MMP expression by RSF when present on the substrate with 120FN. RSF expressed alpha 4 beta 1 integrin, the receptor for CS-1, and the anti-alpha 4 mAb blocked the ability of CS-1 to suppress MMP induction by 120FN. These results show that signals modulating MMP expression and focal contact assembly are regulated independently, and that cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins plays a dominant role in regulating expression of these extracellular matrix-remodeling genes in response to FN. This work demonstrates directly the modular way in which information in the extracellular matrix is detected and processed by cell surface receptors.
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May 01 1995
Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin.
P Huhtala,
P Huhtala
Department of Stomatology, University of California, San Francisco 94143, USA.
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M J Humphries,
M J Humphries
Department of Stomatology, University of California, San Francisco 94143, USA.
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J B McCarthy,
J B McCarthy
Department of Stomatology, University of California, San Francisco 94143, USA.
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P M Tremble,
P M Tremble
Department of Stomatology, University of California, San Francisco 94143, USA.
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Z Werb,
Z Werb
Department of Stomatology, University of California, San Francisco 94143, USA.
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C H Damsky
C H Damsky
Department of Stomatology, University of California, San Francisco 94143, USA.
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P Huhtala
Department of Stomatology, University of California, San Francisco 94143, USA.
M J Humphries
Department of Stomatology, University of California, San Francisco 94143, USA.
J B McCarthy
Department of Stomatology, University of California, San Francisco 94143, USA.
P M Tremble
Department of Stomatology, University of California, San Francisco 94143, USA.
Z Werb
Department of Stomatology, University of California, San Francisco 94143, USA.
C H Damsky
Department of Stomatology, University of California, San Francisco 94143, USA.
Online ISSN: 1540-8140
Print ISSN: 0021-9525
J Cell Biol (1995) 129 (3): 867–879.
Citation
P Huhtala, M J Humphries, J B McCarthy, P M Tremble, Z Werb, C H Damsky; Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin.. J Cell Biol 1 May 1995; 129 (3): 867–879. doi: https://doi.org/10.1083/jcb.129.3.867
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