Fibroblast Growth Factor Receptor-Mediated Activation of AKT-β-Catenin-CBP Pathway Regulates Survival and Proliferation of Murine Hepatoblasts and Hepatic Tumor Initiating Stem Cells

Fibroblast Growth Factor (FGF)-10 promotes the proliferation and survival of murine hepatoblasts during early stages of hepatogenesis through a Wnt-beta-catenin dependent pathway. To determine the mechanism by which this occurs, we expanded primary culture of hepatoblasts enriched for progenitor markers CD133 and CD49f from embryonic day (E) 12.5 fetal liver and an established tumor initiating stem cell line from Mat1a(-/-) livers in media conditioned with recombinant (r) FGF10 or rFGF7. FGF Receptor (R) activation resulted in the downstream activation of MAPK, PI3K-AKT, and beta-catenin pathways, as well as cellular proliferation. Additionally, increased levels of nuclear beta-catenin phosphorylated at Serine-552 in cultured primary hepatoblasts, Mat1a(-/-) cells, and also in ex vivo embryonic liver explants indicate AKT-dependent activation of beta-catenin downstream of FGFR activation; conversely, the addition of AKT inhibitor Ly294002 completely abrogated beta-catenin activation. FGFR activation-induced cell proliferation and survival were also inhibited by the compound ICG-001, a small molecule inhibitor of beta-catenin-CREB Binding Protein (CBP) in hepatoblasts, further indicating a CBP-dependent regulatory mechanism of beta-catenin activity. Conclusion: FGF signaling regulates the proliferation and survival of embryonic and transformed progenitor cells in part through AKT-mediated activation of beta-catenin and downstream interaction with the transcriptional co-activator CBP. Citation: Mavila N, James D, Utley S, Cu N, Coblens O, et al. (2012) Fibroblast Growth Factor Receptor-Mediated Activation of AKT-beta-Catenin-CBP Pathway Regulates Survival and Proliferation of Murine Hepatoblasts and Hepatic Tumor Initiating Stem Cells. PLoS ONE 7(11): e50401. doi:10.1371/journal.pone.0050401