FGF15-FGFR4 Regulates Hippo Signaling Pathway

Hippo signaling pathway is a highly-conserved pathway that regulates cellular proliferation and apoptosis.Hippo signaling pathway also plays an important role in development,organ size maintenance and tumorigenesis suppression.The absences of Hippo pathway components or abnormal activation of transcription co-activator Yap in hepatocytes would result in severe hepatomegaly and finally the development of HCC.Because Hippo Pathway is a strong tumor-suppressor pathway,it has been intensively studied,but the external factors that regulate this pathway remain elusive.We aimed at screening out the external factors that regulate Hippo pathway.We found that endocrine factor FGF15 enhanced Mob1 phosphorylation in murine hepatocytes in a dose-dependent manner.Hence,we identified FGF15 as an activator of Hippo signaling pathway.FGF15 selectively binds to the hepatic receptor FGFR4 and promotes the interaction between FGFR4 and NF2(upstream regulator of MST).Then FGFR4 phosphorylates the Tyrosine residue of NF2 which stabilizes and activates NF2.Interestingly,FGFR4-phosphorylated NF2 to activate Hippo pathway,while ERK pathway was suppressed reciprocally.Finally,we compared the expression of FGFR4 and NF2 in different tumor types to determine the pathological relevance of FGFR4-NF2 in HCC(Hepatocellular Carcinoma)patients.We found that expression of FGFR4 was enhanced and NF2 was down-regulated in most cases.Taken together,our study revealed that FGF15 is an external factor of Hippo signaling pathway.FGF15 activates FGFR4 to phosphorylate NF2,then the FGFR4-NF2 complex activates Hippo pathway.ERK pathway is induced when NF2 is absent.Our finding provided new targets for tumor therapy.