DDR1b Protein Interaction with Talin Regulates Cell Migration

Extract

[...] Furthermore, the BCR protein is free to hydrolyze Rac-GTP to Rac-GDP, which strengthens adhesion to its substrate. On the other hand, in the case of cells that express the DDR1b receptor and are exposed to collagen the DDR1b receptor binds the talin protein and colocalizes with activated integrin b1 at focal adhesions. This results in the stimulation of cellular migration mediated by integrin b1. Furthermore, DDR1b binds the BCR protein, preventing it from hydrolyzing the GTP of the Rac1 protein, which remains in an activated state, and thus enhances cellular migration. [...]

[...] For example, DDR1 and integrin a2b1 cooperate in the process of pancreatic cancer cell diffusion. On the other hand, DDR1 seems to prevent collagen-induced epithelial cell migration by inhibiting the activation of cyclin Cdc42 mediated by integrin a2b1. Thus, although DDR1 is described as an essential contributor in the cancerous and metastatic processes of adhesion and migration, the mechanisms of action and the involvement of integrins are not clearly established. Determining these mechanisms could make the DDR1 factor a therapeutic target in the treatment of these pathological processes. [...]

[...] These results indicate that BCR seems to be closer to the protein DDR1b than to the protein DDR1a in a cellular context (figure 5A). Furthermore, we can see that cells adhering to a collagen I substrate and expressing DDR1b have higher levels of Rac-GTP, the active form of the protein Rac1, than in cells expressing DDR1a (figure 5B). The protein BCR is a protein involved in the cellular migration of cells expressing DDR1b on collagen I since the effective reduction of BCR expression leads to an increase in cellular migration (figures 5C-D) while, on the other hand, the overexpression of BCR in these cells leads to a decrease in cellular migration (figures 5E-F). [...]

[...] In cells, DDR1b, but not DDR1a, colocalizes with talin and ?1-integrin at focal adhesions and enhances cell migration mediated by ?1-integrin. Furthermore, we have shown that DDR1b promotes cell migration by enhancing the activation of Rac1. Functionally, DDR1b interacts with the GTPase activating protein (GAP) Breakpoint cluster region (BCR) reducing its GAP activity and enhancing Rac activation. Our study allowed us to identify DDR1b as a major actor of cell migration, and the talin and BCR proteins are key actors at the interface between integrins and DDR1b in regulating cell migration. [...]

[...] Collagen I contains selective binding motifs for DDRs and integrins; however, the relative contribution of these two receptors in the regulation of cell migration is not clearly established. DDR1 has five isoforms (DDR1a-e), with most cells expressing DDR1a and DDR1b isoforms. We have shown that human embryonic kidney 293 cells expressing DDR1b migrate more than cells expressing DDR1a on a selective substrate for DDRs such as collagen I in vitro. In addition, cells expressing DDR1b have increased lung colonization after injection into the tail vein in mice nude. [...]