Epac1 increases migration of endothelial cells and melanoma cells via FGF2‐mediated paracrine signaling |
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| Authors: | Erdene Baljinnyam Masanari Umemura Christine Chuang Mariana S. De Lorenzo Mizuka Iwatsubo Suzie Chen James S. Goydos Yoshihiro Ishikawa John M. Whitelock Kousaku Iwatsubo |
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| Affiliation: | 1. Department of Cell Biology and Molecular Medicine, New Jersey Medical School‐Rutgers, The State University of New Jersey, , Newark, NJ, USA;2. Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, , Yokohama, Japan;3. The Heart Research Institute, , Newtown, NSW, Australia;4. Susan Lehman Cullman Laboratory for Cancer Research Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, , Piscataway, NJ, USA;5. The Cancer Institute of New Jersey, , New Brunswick, NJ, USA;6. Graduate School of Biomedical Engineering, The University of New South Wales, , Kensington, NSW, Australia |
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| 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. |
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| Keywords: | Epac heparan sulfate human umbilical vein endothelial cells cell– cell communication FGF2 migration angiogenesis paracrine signaling |
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