title: Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling.
abstract: Fibroblast growth factor (FGF2) regulates endothelial and melanoma cell migration. The binding of FGF2 to its receptor requires N-sulfated heparan sulfate (HS) glycosamine. We have previously reported that Epac1, an exchange protein activated by cAMP, increases N-sulfation of HS in melanoma. Therefore, we examined whether Epac1 regulates FGF2-mediated cell-cell communication. Conditioned medium (CM) of melanoma cells with abundant expression of Epac1 increased migration of human umbilical endothelial cells (HUVEC) and melanoma cells with poor expression of Epac1. CM-induced increase in migration was inhibited by antagonizing FGF2, by the removal of HS and by the knockdown of Epac1. In addition, knockdown of Epac1 suppressed the binding of FGF2 to FGF receptor in HUVEC, and in vivo angiogenesis in melanoma. Furthermore, knockdown of Epac1 reduced N-sulfation of HS chains attached to perlecan, a major secreted type of HS proteoglycan that mediates the binding of FGF2 to FGF receptor. These data suggested that Epac1 in melanoma cells regulates melanoma progression via the HS-FGF2-mediated cell-cell communication.
authors.affiliation: Department of Cell Biology and Molecular Medicine, New Jersey Medical School-Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Erdene
authors.initials: E
authors.lastname: Baljinnyam
authors.forename: Masanari
authors.initials: M
authors.lastname: Umemura
authors.forename: Christine
authors.initials: C
authors.lastname: Chuang
authors.forename: Mariana S
authors.initials: MS
authors.lastname: De Lorenzo
authors.forename: Mizuka
authors.initials: M
authors.lastname: Iwatsubo
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
authors.forename: James S
authors.initials: JS
authors.lastname: Goydos
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: John M
authors.initials: JM
authors.lastname: Whitelock
authors.forename: Kousaku
authors.initials: K
authors.lastname: Iwatsubo
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis* / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; C116122:RAPGEF3 protein, human; D016222:Fibroblast Growth Factor 2
keywords: Epac; FGF2; angiogenesis; cell-cell communication; heparan sulfate; human umbilical vein endothelial cells; migration; paracrine signaling
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