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.
Program of Molecular Neurobiology, Institute of Biotechnology, and Department of Biosciences, University of Helsinki, Helsinki FIN-00014, Finland. Henri.Huttunen@helsinki.fi
Henri J
HJ
Huttunen
Carole
C
Fages
Juha
J
Kuja-Panula
Anne J
AJ
Ridley
Heikki
H
Rauvala
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