The Regulation Of Hippo Pathway By The SUMOylation

Hippo pathway plays a key role in cellular homeostasis,it regulates the organ size,cell proliferation and apoptosis.The Hippo pathway is highly conserved in mammals,which is consist of MST 1/2,Sav1,Lats 1/2,MOB1a/b and transcriptional co-activator YAP/TAZ,it is a kinase-mediated cascade reaction.Hippo pathway can be effected by some extracellular signal,such as LPA,glucose and the cell density.This pathway involves in many diseases,it can found the foundation of researching the tumor and other diseases by studying the Hippo pathway,besides,studying Hippo pathway can provide the theory of treatment.In our study,we screened a SUMO isopeptidase USPL1 by Dual-Luciferase Reporter Assay.The USPL1 can enhance the activation of YAP and TAZ.Our study shows that the USPL1 inhibits the Latsl/2-mediate direct phosphorylation on YAP Ser127,it can effect the location of YAP in cells.Besides,the USPL1 increase the mRNA level of the Hippo pathway downstream transcription factors.We proves the USPL1 can bind with Latsl/2 directly by doing Co-Immunoprecipitation(Co-IP)experiment.The experiments also show that the Latsl can be regulated by SUMOylation.The results show that the can be regulated by SUMOylation.In further study,we find the SUMOylation E3 protein ligase PIAS1 can inhibit the activation of YAP/TAZ,it effects the location of YAP in cells by promoting the Latsl/2-mediate direct phosphorylation on YAP Ser127.The PIAS1 decrease the mRNA level of the Hippo pathway downstream transcription factors.The Co-IP experiments show that PIAS1 binds with LATS1/2 and YAP.Moreover,the SUMOylation E2 conjugating enzyme UBC9 have effect on the Hippo pathway as well.All these data demonstrate the SUMOylation can regulate the Hippo pathway.SUMOylation plays a key role in cell signal regulation,it can regulate many important pathway,such as NF-Kb pathway and JAK-STAT pathway.In our research,we found two kind of protein which related to the SUMOylation—USPL1 and PIAS1.Both of them play important roles in regulating Hippo pathway.However,it is still unclear how does the SUMOylation regulate the Hippo pathway.Our study identifies the correlation between SUMOylation and Hippo pathway,which supplies a new target for the cancer treatment and drug discovery.