CCBIO seminar: Nuno M. Coelho
DDR1 expression, collagen-dependent activation and signaling in cancer and tissue fibrosis
Nuno M. Coelho
Matrix Dynamics Group, University of Toronto, ON, Canada
The discoidin domain receptor 1 (DDR1) is a tyrosine kinase, collagen adhesion mechanoreceptor associated with fibrotic conditions of kidney, liver, lung and perivascular tissues. We reported earlier a role for DDR1 in mechanical realignment of collagen by traction forces, which is consistent with the increased expression of DDR1 in several different types of cancer and fibrotic conditions. Our main findings are that DDR1 clustering, activation, and interaction with myosin IIA filaments enhance the collagen tractional remodeling that is important for collagen alignment in cancer and fibrosis. DDR1 overexpression is associated with β1 integrin activation but little is known about the downstream pathways activated by DDR1 that regulate integrin-dependent signals that contribute to tissue fibrosis. We considered that DDR1 contributes to cancer and tissue fibrosis by regulating β1 integrin-dependent mitogen-activated protein kinase (MAPK) signaling. DDR1 over-expression reduced extracellular signal-regulated kinase (ERK) phosphorylation 5-fold in cells expressing β1 integrin when plated on collagen, while plating on fibronectin or inhibition of DDR1 phosphorylation with nilotinib rescued ERK phosphorylation. A phospho-site screen indicated that DDR1 activation inhibits β1 integrin-dependent ERK signaling through regulation of focal adhesion kinase (FAK) autophosphorylation. 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. Our data indicate that DDR1 expression and adhesion to collagen control β1 integrin-dependent MAPK signaling that could contribute to cancer and tissue fibrosis.
Chairperson: Marion Kusche-Gullberg, Department of Biomedicine