Direct Binding and Activation of Receptor Tyrosine Kinases by Collagen

It is now well-established that collagen and other components of the extracellular matrix play an important role in the control of cell shape, cell migration, cell proliferation, and differentiation. The primary cellular receptors for collagens are α2β1 or α1β1 integrins (Kuhn and Eble 1994xKuhn, K and Eble, J. Trends Cell Biol. 1994; 4: 256–261Abstract | Full Text PDF | PubMed | Scopus (98)See all ReferencesKuhn and Eble 1994). Analysis of signaling pathways that are activated by engagement of integrins by extracellular matrix proteins has demonstrated a remarkable similarity to the signaling pathways activated by growth factor receptors (Clark and Brugge 1995xClark, E.A and Brugge, J.S. Science. 1995; 268: 233–239Crossref | PubMedSee all ReferencesClark and Brugge 1995). This includes the canonical Ras/MAP kinase pathway, a signaling pathway mediated by PI-3 kinase and by Akt/PKB, as well as activation of phospholipase Cγ and phosphoinositide metabolism, among other intracellular events. There is good evidence for synergy between signaling pathways that are activated by growth factors and signaling pathways downstream of integrins. In addition, it is well known that normal growth control requires both anchorage dependence and tightly regulated signaling via growth factor receptors. The realization that collagen, one of the most abundant proteins in vertebrates, can activate a family of receptor tyrosine kinases, provides further evidence that signaling via integrins and receptor tyrosine kinases is regulated in a coordinated fashion.It is proposed that collagen binds to DDR receptors in a fundamentally different manner than growth factor binding to their receptors. It is possible that the low-affinity interaction between collagen and DDR receptors is secondary to collagen's primary interaction with integrins. According to this scenario, DDR receptors would function as signaling components of a multi-integrin complex that transmits the intracellular signal initiated at the cell surface by engagement of integrins by collagen and perhaps also other extracellular matrix proteins (Figure 2Figure 2). It is noteworthy that an association between αvβ3 integrin and IRS1, a major substrate of insulin receptor, was detected in lysates of insulin-stimulated cells (Vuori and Ruoslahti 1994xVuori, K and Ruoslahti, E. Science. 1994; 266: 1576–1578Crossref | PubMedSee all ReferencesVuori and Ruoslahti 1994).These two reports provide convincing evidence for activation of DDR receptors by collagen fibers, although the biological significance of the interaction remains to be determined. In addition, it is puzzling that the docking protein Shc binds to the activated DDR1b isoform, yet MAP kinase is not activated in response to stimulation of DDR receptors by collagen. Finally, the extremely slow kinetics of tyrosine phosphorylation of the DDR receptors in response to collagen stimulation is both unique and unexplained.Perhaps the most intriguing result of the recent observations is that collagen-induced expression of MMP1 is mediated by DDR2 (Vogel et al. 1997xVogel, W, Gish, G.D, Alves, F, and Pawson, T. Mol. Cell. 1997; 1: 13–23Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesVogel et al. 1997). It is proposed that overexpression of DDR1 receptors in breast, ovarian, and other epithelial tumors may be responsible for overexpression of MMP1 in the tumor cells which in turn will degrade collagen molecules surrounding the tumor, thus allowing tumor cell escape and metastasis. The validation of this hypothesis in animal models will be of significant interest, and generation of specific inhibitors for DDR1 and DDR2 receptors may prove to be therapeutically beneficial for treatments of metastatic diseases and for scars associated with wound healing.