title: 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.
abstract: Fibroblast Growth Factor (FGF)-10 promotes the proliferation and survival of murine hepatoblasts during early stages of hepatogenesis through a Wnt-β-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 β-catenin pathways, as well as cellular proliferation. Additionally, increased levels of nuclear β-catenin phosphorylated at Serine-552 in cultured primary hepatoblasts, Mat1a(-/-) cells, and also in ex vivo embryonic liver explants indicate AKT-dependent activation of β-catenin downstream of FGFR activation; conversely, the addition of AKT inhibitor Ly294002 completely abrogated β-catenin activation. FGFR activation-induced cell proliferation and survival were also inhibited by the compound ICG-001, a small molecule inhibitor of β-catenin-CREB Binding Protein (CBP) in hepatoblasts, further indicating a CBP-dependent regulatory mechanism of β-catenin activity.
  
  
  CONCLUSIONS
  FGF signaling regulates the proliferation and survival of embryonic and transformed progenitor cells in part through AKT-mediated activation of β-catenin and downstream interaction with the transcriptional co-activator CBP.
authors: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Nirmala
authors: N
authors: Mavila
authors: David
authors: D
authors: James
authors: Sarah
authors: S
authors: Utley
authors: Nguyen
authors: N
authors: Cu
authors: Orly
authors: O
authors: Coblens
authors: Katrina
authors: K
authors: Mak
authors: C Bart
authors: CB
authors: Rountree
authors: Michael
authors: M
authors: Kahn
authors: Kasper S
authors: KS
authors: Wang
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D053595:Embryonic Stem Cells / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D008716:Methionine Adenosyltransferase / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D051176:beta Catenin; D050882:CREB-Binding Protein; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases