br DDR mediated signaling DDRs initiate
DDR-mediated signaling DDRs initiate signaling pathways in a context and cell type-dependent manner. For instance, DDR1 was reported to activate ERK in vascular smooth muscle mcc950 (Lu et al., 2011), to inhibit ERK in mesangial cells (Curat and Vogel, 2002), and to have no effect on ERK activation in T47D breast cancer cells (L'Hote et al., 2002). Furthermore DDR1 was reported to both promote and inhibit epithelial-to-mesenchymal transition (EMT) in a ligand- and cell type-dependent manner. In pancreatic cancer cells, DDR1, together with integrin α2β1, promotes cell scattering on collagen I and increases the mesenchymal marker N-cadherin (Shintani et al., 2008). By contrast, DDR1 inhibits integrin α2β1-mediated migration and spreading and stabilizes the epithelial marker E-cadherin in Madin–Darby canine kidney (MDCK) cells (Wang et al., 2006, Yeh et al., 2009, Eswaramoorthy et al., 2010). Of interest, some DDR1-mediated cell functions are independent of collagen binding or receptor kinase activity. For instance, DDR1 was reported to support collective cell migration by decreasing the activity of actomyosin at cell–cell contacts. This function was dependent on the DDR1 carboxyl terminus which contains a PDZ binding motif and interacts with the cell polarity protein Par3/Par6 complex (Hidalgo-Carcedo et al., 2011). Like DDR1, DDR2 was also shown to promote EMT. In this context, EMT in MDCK cells is accompanied by increased DDR2 expression (Maeyama et al., 2008); TGF-β promotes DDR2 expression, and collagen I-induced EMT is prevented by downregulating DDR2 expression (Walsh et al., 2011). Furthermore, collagen I-mediated DDR2 activation increases the stability of the EMT driver SNAIL1 and promotes breast cancer cell invasion in vitro and increased metastasis in vivo (Zhang et al., 2013a).
DDRs cross-talk with receptors and growth factors In addition to mediating direct collagen-dependent signaling, DDRs can also modulate signaling pathways initiated by other matrix receptors (e.g., integrins), cytokines (e.g., TGF-β) and transmembrane receptors (e.g., insulin receptor and Notch1). Cross-talk between DDRs and integrin is complex and influences multiple processes including cell adhesion and differentiation. DDR1 can both potentiate and inhibit integrin-mediated signaling. DDR1 cooperates with integrin α2β1 in maintaining mouse embryonic stem cells undifferentiated via activation of selective collagen–DDR and collagen–integrin mediated signaling pathways that ultimately converge to the self-renewal controlling molecule Bim-1 (Suh and Han, 2011). Moreover, overexpression of DDR1 or DDR2 in cells expressing the collagen binding receptors integrins α1β1 and α2β1, results in enhanced integrin-mediated adhesion to collagen due to increased integrin activation rather than increased integrin expression levels (Xu et al., 2012). In contrast to these findings, DDR1 has been shown to counteract integrin-mediated signaling and promote epithelial cell differentiation (Yeh et al., 2012). In MDCK cells, for example, integrin β1 promotes cell dedifferentiation by downregulating E-cadherin, while DDR1 promotes cell differentiation by increasing membrane stability of E-cadherin (Yeh et al., 2012). Thus DDR1-integrin cross-talk is highly dependent on the type of integrins the cells express and the cell type. DDRs can also modulate signaling initiated by growth factors. Cross-talk between DDR1 and TGF-β is critical for proper growth and patterning of mammary gland in mice. In this context, TGF-β negatively regulates ductal extension and lateral branching in the mammary gland by promoting Wnt5a expression and DDR1 phosphorylation (Roarty and Serra, 2007). Wnt5a acts as an upstream regulator of DDR1 promoting collagen-induced DDR1 phosphorylation in human mammary epithelial cells. In addition, levels of Wnt5a are directly associated to increased cell adhesion and reduced cell migration on collagen (Jonsson and Andersson, 2001), suggesting that Wnt5a might control two important cell functions by regulating the phosphorylation and activation of DDR1.