title: YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis.
abstract: Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulatesIL6STgene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain whyAPCloss is a more potent initiating event than the mere activation ofCTNNB1.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, CA 92093.|Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.|Department of Pathology, University of California, San Diego, La Jolla, CA 92093.|Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Moroishi
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.|Sanford Burnham Prebys Medical Discovery Institute, National Cancer Institute-Designated Cancer Center, La Jolla, CA 92037.
authors.forename: Petrus R
authors.initials: PR
authors.lastname: de Jong
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Michal
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: German Cancer Consortium, 69120 Heidelberg, Germany.|Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt on Main, Germany.|German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Britta Moyo
authors.initials: BM
authors.lastname: Grebbin
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093.|State Key Laboratory of Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Xu
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz A-8036, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Golob-Schwarzl
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz A-8036, Austria.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schweiger
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, CA 92093.|Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.|Department of Pathology, University of California, San Diego, La Jolla, CA 92093.|Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, 06030.
authors.forename: Kepeng
authors.initials: K
authors.lastname: Wang
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, CA 92093.|Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.|Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Caro
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.|Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.|Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, 1090 Vienna, Austria.|Department for Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: German Cancer Consortium, 69120 Heidelberg, Germany.|Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt on Main, Germany.|German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Henner F
authors.initials: HF
authors.lastname: Farin
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz A-8036, Austria.|Department of Pathology, Otto-von-Guericke University of Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, 5110 Oberndorf, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, CA 92093; karinoffice@ucsd.edu.|Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.|Department of Pathology, University of California, San Diego, La Jolla, CA 92093.|Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D018797:Cell Cycle Proteins; C494199:IL6ST protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D051176:beta Catenin; D050822:Cytokine Receptor gp130
keywords: IL-6ST/gp130; STAT3; YAP; adenomatous polyposis coli; colorectal cancer