title: An RGD motif present in cadherin 17 induces integrin activation and tumor growth.
abstract: 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 β1 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 α2β1 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.
authors.affiliation: From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Rubén A
authors.initials: RA
authors.lastname: Bartolomé
authors.affiliation: From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Peláez-García
authors.affiliation: Protein Alternatives SL, Tres Cantos, Madrid, Spain, and.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Gomez
authors.affiliation: From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Torres
authors.affiliation: the Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Fernandez-Aceñero
authors.affiliation: From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Escudero-Paniagua
authors.affiliation: Protein Alternatives SL, Tres Cantos, Madrid, Spain, and.
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Imbaud
authors.affiliation: From the Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain, icasal@cib.csic.es.
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Casal
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000473:pathology; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009362:Neoplasm Metastasis; D009842:Oligopeptides; D010190:Pancreatic Neoplasms / Q000473:pathology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: C490584:CDH17 protein, human; D015820:Cadherins; D038982:Integrin alpha2beta1; D016023:Integrins; D008024:Ligands; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid
keywords: Cadherin; Cell Signaling; Colon Cancer; Integrin; RGD Motif; Tumor Metastasis