More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1(YAP1) and its close paralog TAZ,...More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1(YAP1) and its close paralog TAZ, transcriptional co-activator with a PDZbinding motif, function as key effectors negatively controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In various cancers, Hippo pathway cross-talks with pro- or anti-tumorigenic pathways such as GPCR, Wnt/β-catenin, Notch and TGF-β signaling and is deregulated by multiple factors including cell density/junction and micro RNAs. As YAP1 expression is significantly associated with poor prognosis of gastric and other gastrointestinal cancers, detailed delineation of Hippo regulation in tumorigenesis provides novel insight for therapeutic intervention. In current review, we summarized the recent research progresses on the deregulation of Hippo pathway in the gastrointestinal tract including stomach and discuss the molecular consequences leading to tumorigenesis.展开更多
Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth.This pathway is activated in response to cell cycle arrest signals(cell polar...Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth.This pathway is activated in response to cell cycle arrest signals(cell polarity,transduction,and DNA damage)and limited by growth factors or mitogens associated with EGF and LPA.The major pathway consists of the central kinase of Ste20 MAPK(Saccharomyces cerevisiae),Hpo(Drosophila melanogaster)or MST kinases(mammalian)that activates the mammalian AGC kinase dmWts or LATS effector(MST and LATS).YAP in the nucleus work as a cofactor for a wide range of transcription factors involved in proliferation(TEA domain family,TEAD1-4),stem cells(Oct4 mononuclear factor and SMAD-related TGFb effector),differentiation(RUNX1),and Cell cycle/apoptosis control(p53,p63,and p73 family members).This is due to the diverse roles of YAP and may limit tumor progression and establishment.TEAD also coordinates various signal transduction pathways such as Hippo,WNT,TGFb and EGFR,and effects on lack of regulation of TEAD cancerous genes,such as KRAS,BRAF,LKB1,NF2 and MYC,which play essential roles in tumor progression,metastasis,cancer metabolism,immunity,and drug resistance.However,RAS signaling is a pivotal factor in the inactivation of Hippo,which controls EGFR-RAS-RAF-MEK-ERKmediated interaction of Hippo signaling.Thus,the loss of the Hippo pathway may have significant consequences on the targets of RAS-RAF mutations in cancer.展开更多
基金General Research Fund(No.2140855RGC Reference No.CUHK14114414)from The Research Grants Council of Hong Kong+1 种基金National Natural Science Grant No.81201591 from ChinaDirect Grant for Research No.2014.2.002 from The Chinese University of Hong Kong
文摘More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1(YAP1) and its close paralog TAZ, transcriptional co-activator with a PDZbinding motif, function as key effectors negatively controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In various cancers, Hippo pathway cross-talks with pro- or anti-tumorigenic pathways such as GPCR, Wnt/β-catenin, Notch and TGF-β signaling and is deregulated by multiple factors including cell density/junction and micro RNAs. As YAP1 expression is significantly associated with poor prognosis of gastric and other gastrointestinal cancers, detailed delineation of Hippo regulation in tumorigenesis provides novel insight for therapeutic intervention. In current review, we summarized the recent research progresses on the deregulation of Hippo pathway in the gastrointestinal tract including stomach and discuss the molecular consequences leading to tumorigenesis.
文摘Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth.This pathway is activated in response to cell cycle arrest signals(cell polarity,transduction,and DNA damage)and limited by growth factors or mitogens associated with EGF and LPA.The major pathway consists of the central kinase of Ste20 MAPK(Saccharomyces cerevisiae),Hpo(Drosophila melanogaster)or MST kinases(mammalian)that activates the mammalian AGC kinase dmWts or LATS effector(MST and LATS).YAP in the nucleus work as a cofactor for a wide range of transcription factors involved in proliferation(TEA domain family,TEAD1-4),stem cells(Oct4 mononuclear factor and SMAD-related TGFb effector),differentiation(RUNX1),and Cell cycle/apoptosis control(p53,p63,and p73 family members).This is due to the diverse roles of YAP and may limit tumor progression and establishment.TEAD also coordinates various signal transduction pathways such as Hippo,WNT,TGFb and EGFR,and effects on lack of regulation of TEAD cancerous genes,such as KRAS,BRAF,LKB1,NF2 and MYC,which play essential roles in tumor progression,metastasis,cancer metabolism,immunity,and drug resistance.However,RAS signaling is a pivotal factor in the inactivation of Hippo,which controls EGFR-RAS-RAF-MEK-ERKmediated interaction of Hippo signaling.Thus,the loss of the Hippo pathway may have significant consequences on the targets of RAS-RAF mutations in cancer.
