Epac1, an exchange protein activated by cAMP, increases cell migration through syndecan clustering, PI3K activation and heparan sulphate production.

Abstract

Background: The role of epac1, an exchange protein activated by cAMP, in melanoma migration is largely unknown. Heparan sulfate (HS), a major ECM, and syndecan2, a HS‐binding protein on the cell surface, play important roles in regulating such migration. Syndecan2, when activated, translocates to lipid‐rich plasma microdomains, known as lipid rafts. We thus examined the role of epac1 in HS production and syndecan2 translocation in melanoma migration.Methods: SK‐MEL‐2, a human melanoma cell line, and migration assays with Boyden chambers were employed.Results: Activation of Epac1 by adenoviral Epac1 overexpression or 8pMeOPT, an Epac‐specific cAMP analog, significantly increased cell migration in a time‐ and dose‐dependent manner. Epac1 also increased HS production by 3.5‐fold, and the removal of HS abolished Epac1‐induced migration. Epac1 also increased expression of N‐deacetylase/N‐sulfotransferase‐1 (NDST‐1), a key synthetic enzyme for HS. Sucrose gradient fractionation showed that Epac1 markedly increased syndecan2 translocation to rafts. In addition, disruption of rafts with lipid depletion abolished Epac1‐induced migration.Summary: Epac1 increased migration in malignant melanoma through HS production and syndecan2 translocation to rafts.