Galownia, Niki C. and Kushiro, Keiichiro and Gong, Yuan and Asthagiri, Anand R. (2007) Selective Desensitization of Growth Factor Signaling by Cell Adhesion to Fibronectin. Journal of Biological Chemistry, 282 (30). pp. 21758-21766. ISSN 0021-9258 http://resolver.caltech.edu/CaltechAUTHORS:GALjbc07
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Cell adhesion to the extracellular matrix is required to execute growth factor (GF)-mediated cell behaviors, such as proliferation. A major underlying mechanism is that cell adhesion enhances GF-mediated intracellular signals, such as extracellular signal-regulated kinase (Erk). However, because GFs use distinct mechanisms to activate Ras-Erk signaling, it is unclear whether adhesion-mediated enhancement of Erk signaling is universal to all GFs. We examined this issue by quantifying the dynamics of Erk signaling induced by epidermal growth factor, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) in NIH-3T3 fibroblasts. Adhesion to fibronectin-coated surfaces enhances Erk signaling elicited by epidermal growth factor but not by bFGF or PDGF. Unexpectedly, adhesion is not always a positive influence on GF-mediated signaling. At critical subsaturating doses of PDGF or bFGF, cell adhesion ablates Erk signaling; that is, adhesion desensitizes the cell to GF stimulation, rendering the signaling pathway unresponsive to GF. Interestingly, the timing of growth factor stimulation proved critical to the desensitization process. Erk activation significantly improved only when pre-exposure to adhesion was completely eliminated; thus, concurrent stimulation by GF and adhesion was able to partially rescue adhesion-mediated desensitization of PDGF- and bFGF-mediated Erk and Akt signaling. These findings suggest that adhesion-mediated desensitization occurs with rapid kinetics and targets a regulatory point upstream of Ras and proximal to GF receptor activation. Thus, adhesion-dependent Erk signaling is not universal to all GFs but, rather, is GF-specific with quantitative features that depend strongly on the dose and timing of GF exposure.
|Additional Information:||Copyright © 2007 by the American Society for Biochemistry and Molecular Biology. Received for publication, April 30, 2006. Originally published In Press as doi:10.1074/jbc.M703577200 on May 31, 2007. We thank the members of the Asthagiri group for helpful discussions and suggestions. This work was supported by National Institutes of Health Grant EB005214 and by the Center for Science and Engineering of Materials at Caltech. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.|
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|Deposited On:||17 Aug 2007|
|Last Modified:||26 Dec 2012 09:39|
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