title: YAP/TAZ-Mediated Upregulation of GAB2 Leads to Increased Sensitivity to Growth Factor-Induced Activation of the PI3K Pathway.
abstract: The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor-induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growthin vivoIn addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer.Cancer Res; 77(7); 1637-48. ©2017 AACR.
authors.affiliation: Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. wang1980-55@163.com.|Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.|Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chao
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kang Jin
authors.initials: KJ
authors.lastname: Jeong
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Nattapon
authors.initials: N
authors.lastname: Panupinthu
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Department of Veterinary Medicine & Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mihai Mike
authors.initials: MM
authors.lastname: Gagea
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick Kwok Shing
authors.initials: PK
authors.lastname: Ng
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D011166:Porphyrins / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D015854:Up-Regulation; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011166:Porphyrins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins; C490895:GAB2 protein, human; C551991:WWTR1 protein, human; C088374:YAP1 protein, human