Abstract
Cell anchorage strongly affects the signal transduction cascade initiated by peptide mitogens. For both epidermal growth factor and platelet-derived growth factor, activation of the consensus mitogen-activated protein kinase cascade is impaired when cells are held in suspension as compared with cells anchored to a fibronectin substratum. Upstream events in the signaling cascade, including tyrosine phosphorylation of the mitogen receptor and GTP loading of Ras, are similar in anchored and suspended cells. However, propagation of the signal to Raf and subsequently to the downstream kinases MEK and mitogen-activated protein kinase is markedly attenuated in suspended cells. Thus, there seems to be a distinct anchorage-dependent step between Ras and Raf in the signaling cascade initiated by peptide mitogens. These observations may have important implications for understanding the anchorage dependence of cell growth.
Highlights
Cell anchorage to the proteins of the extracellular matrix is known to have profound effects on cell differentiation [1, 2], cell growth [3], and apoptosis [4]
Because integrins directly activate elements of the MAP kinase cascade, it is of interest to ask whether integrin-mediated cell anchorage can regulate the action of soluble mitogens on this cascade
We have examined several steps in the signal transduction pathway leading from receptor tyrosine kinases to Ras and to the downstream kinases
Summary
Cell anchorage to the proteins of the extracellular matrix is known to have profound effects on cell differentiation [1, 2], cell growth [3], and apoptosis [4]. After 10 min of cell adhesion to fibronectin-coated substrata, when the cells were fully attached but not spread, there was a strong adhesion-mediated activation of MAP kinase; EGF stimulation caused tyrosine phosphorylation of EGF-R and further stimulated MAP kinase (Fig. 1B, lanes 3 and 4).
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