title: Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP.
abstract: The insulin/IGF signaling (IIS) pathway is a potent inducer of cell proliferation in normal development and in cancer. The mechanism by which this occurs, however, is not completely understood. The Hippo signaling pathway regulates cell proliferation via the transcriptional co-activator Yorkie/YAP, however the signaling inputs regulating Hippo activity are not fully elucidated. Here we present evidence linking these two conserved, oncogenic pathways in Drosophila and in mammalian cells. We find that activation of IIS and of Yorkie signaling correlate positively in hepatocellular carcinoma. We show that IIS activates Yorkie in vivo, and that Yorkie plays an important role in the ability of IIS to drive cell proliferation. Interestingly, we also find the converse--that Yorkie signaling activates components of the insulin/TOR pathway. In sum, this crosstalk between IIS and Yorkie leads to coordinated regulation of these two oncogenic pathways.
authors.affiliation: German Cancer Research Center, DKFZ, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Straßburger
authors.forename: Marcel
authors.initials: M
authors.lastname: Tiebe
authors.forename: Federico
authors.initials: F
authors.lastname: Pinna
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Aurelio A
authors.initials: AA
authors.lastname: Teleman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D013045:Species Specificity; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013002:Somatomedins; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C456659:YY1AP1 protein, human; C486223:Yap1 protein, mouse; C503814:Yki protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases