Cooperation of Epac1/Rap1/Akt and PKA in prostaglandin E2-induced proliferation of human umbilical cord bloodderived mesenchymal stem cells: involvement of c-Myc and VEGF expression

Author(s): Jang MW, Yun SP, Park JH,Ryu JM, Lee JH, et al.


Prostaglandin E(2) (PGE(2)) is well known to regulate cell functions through cAMP; however, the role of exchange protein directly activated by cAMP (Epac1) and protein kinase A (PKA) in modulating such functions is unknown in human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). Therefore, we investigated the relationship between Epac1 and PKA during PGE(2)-induced hUCB-MSC proliferation and its related signaling pathways. PGE(2) increased cell proliferation, and E-type prostaglandin (EP) 2 receptor mRNA expression level and activated cAMP generation, which were blocked by EP2 receptor selective antagonist AH 6809. PGE(2) increased Epac1 expression, Ras-related protein 1 (Rap1) activation level, and Akt phosphorylation, which were inhibited by AH 6809, adenylyl cyclase inhibitor SQ 22536, and Epac1/Rap1-specific siRNA. Also, PGE(2) increased PKA activity, which was inhibited by AH 6809, SQ 22536, and PKA inhibitor PKI. HUCB-MSCs were incubated with the Epac agonist 8-pCPT-cAMP or the PKA agonist 6-phe-cAMP to examine whether Epac1/Rap1/Akt activation was independent of PKA activation. 8-pCPT-cAMP increased Akt phosphorylation but not PKA activity. 6-Phe-cAMP increased PKA activity, but not Akt phosphorylation. Additionally, an Akt inhibitor or PKA inhibitor (PKI) did not block the PGE(2) -induced increase in PKA activity or Akt phosphorylation, respectively. Moreover, PGE(2) increased glycogen synthase kinase (GSK)-3β phosphorylation and nuclear translocation of active-β-catenin, which were inhibited by Akt inhibitor or/and PKI. PGE(2) increased c-Myc and vascular endothelial growth factor (VEGF) expression levels, which were blocked by β-catenin siRNA. In conclusion, PGE(2) stimulated hUCB-MSC proliferation through β-catenin-mediated c-Myc and VEGF expression via Epac/Rap1/Akt and PKA cooperation.

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