In this study we now show that deposition of the mesenchymal matrix marker, tenascin-C (TN-C), is mediated through beta3 expression and activation of Src. There was a striking upregulation of TN-C matrix organization in cell lines expressing beta3 and activated Src when compared to cell lines with neither of these attributes. When beta3 function was suppressed so was the deposition of TN-C. The same was true for function and activation of Src. When Src was inactive, the deposition of TN-C was low. We also determined that one of the downstream effectors of Src, MAPK, was also required to promote TN-C deposition. When MAPK activation was inhibited, TN-C deposition was also decreased. MMP activation is also implicated in TN-C deposition. The broad spectrum MMP inhibitor, GM6001, suppressed TN-C organization. These results indicate that beta3 integrin ligand binding and the activation of the Src/MAPK/MMP pathway modulate deposition of TN-C. (C) 2004 Elsevier Inc. All rights reserved.