An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth

Background: The interaction between cadherin 17 and 21 integrin promotes cell adhesion and proliferation. Results: Cadherin 17 contains an RGD motif that constitutes the critical switch for integrin binding and activation. Conclusion: The cadherin RGD motif is a critical ligand for tumor growth and metastasis. Significance: Cadherin 17 is the first known integrin-ligand RGD-cadherin. Other RGD-cadherins might play important roles in cancer metastasis. Little is known about the mechanism of integrin activation by cadherin 17 (CDH17). Here we observed the presence of a tri-peptide motif, RGD, in domain 6 of the human CDH17 sequence and other cadherins such as cadherin 5 and cadherin 6. The use of CDH17 RAD mutants demonstrated a considerable decrease of proliferation and adhesion in RKO and KM12SM colon cancer cells. Furthermore, RGD peptides inhibited the adhesion of both cell lines to recombinant CDH17 domain 6. The RGD motif added exogenously to the cells provoked a change in 1 integrin to an active, high-affinity conformation and an increase in focal adhesion kinase and ERK1/2 activation. In vivo experiments with Swiss nude mice demonstrated that cancer cells expressing the CDH17 RAD mutant showed a considerable delay in tumor growth and liver homing. CDH17 RGD effects were also active in pancreatic cancer cells. Our results suggest that 21 integrin interacts with two different ligands, collagen IV and CDH17, using two different binding sites. In summary, the RGD binding motif constitutes a switch for integrin pathway activation and shows a novel capacity of CDH17 as an integrin ligand. This motif could be targeted to avoid metastatic dissemination in tumors overexpressing CDH17 and other RGD-containing cadherins.