DDR1 regulates ß1 integrin-dependent MAPK signaling
DDR1 and the ß1 integrin are matrix receptors that initiate discrete, adhesion-dependent signaling pathways. DDR1 is tyrosine-phosphorylated after binding to fibrillar collagen, while ß1 integrin binding to collagen activates the mitogen-activated protein kinase pathways (MAPK). While the DDR1 and integrin signaling pathways have been intensively examined in isolation, little is known about their potential functional interactions. We hypothesized that collagen-induced DDR1 activation affects ß1 integrin-dependent MAPK signaling. DDR1 over-expression reduced ERK phosphorylation 5-fold in cells expressing the ß1 integrin when plated on collagen, while plating on fibronectin or inhibition of DDR1 phosphorylation with nilotinib rescued ERK phosphorylation. To analyze the effect of DDR1 expression levels on MAPK signaling, we created clonally-derived, ß1 integrin null GD25 cell lines with three different levels of DDR1 expression (low, medium, high). DDR1 expression levels and activation were associated with down-regulation of ERK and c-Jun but there was no effect on p38. A phospho-site screen indicated that DDR1 expression levels and activation inhibit ß1 integrin-dependent ERK signaling through phosphorylation of the focal adhesion kinase. Further, in FAK null mouse embryonic fibroblasts, and in cells treated with a FAK inhibitor, collagen-induced ERK activation was reduced, indicating that collagen-induced ERK activation is dependent on FAK. We conclude that DDR1 regulates ß1 integrin-dependent ERK signaling, possibly through FAK.
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