Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis.
Amphoterin has been suggested to regulate invasive process extension and cell migration in tumor cells and embryonic neurons through binding to receptor for advanced glycation end products (RAGE), a multiligand transmembrane receptor belonging to the immunoglobulin superfamily. In this study, we identify a COOH-terminal motif in amphoterin (amino acids 150-183) that is responsible for RAGE binding. We show that as a surface-bound ligand, this part of amphoterin is sufficient to induce RAGE-dependent process extension, suggesting a role in the regulation of cell motility. When applied in solution, the RAGE-binding COOH-terminal motif of amphoterin efficiently inhibits process extension and transendothelial migration of tumor cells. Furthermore, in an in vivo model, the corresponding synthetic peptide significantly suppresses formation of lung metastases. Taken together, these results suggest that amphoterin binds to RAGE through a COOH-terminal motif that can be used as an efficient inhibitor to block invasive migration of tumor cells.
Huttunen
Henri J
HJ
Program of Molecular Neurobiology, Institute of Biotechnology, and Department of Biosciences, University of Helsinki, Helsinki FIN-00014, Finland. Henri.Huttunen@helsinki.fi
Fages
Carole
C
Kuja-Panula
Juha
J
Ridley
Anne J
AJ
Rauvala
Heikki
H
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008969:Molecular Sequence Data; D016501:Neurites / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism* / Q000502:physiology; D017386:Sequence Homology, Amino Acid
D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic