title: eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth.
abstract: In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization, and cell-cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5A-PEAK1 signaling. YAP1/TAZ coimmunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell-associated transcription factors (STF) including Oct4, Nanog, c-Myc, and TEAD, thereby decreasing three-dimensional (3D) tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5A-PEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity.Cancer Res; 77(8); 1997-2007. ©2017 AACR.
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Jan
authors.initials: J
authors.lastname: Strnadel
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Ken
authors.initials: K
authors.lastname: Fujimura
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Huawei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Meghan
authors.initials: M
authors.lastname: Wyse
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Tracy
authors.initials: T
authors.lastname: Wright
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Emilie
authors.initials: E
authors.lastname: Gross
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Carlos
authors.initials: C
authors.lastname: Peinado
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.|Department of Pharmacology, University of California, San Diego, La Jolla, California.
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Jack
authors.initials: J
authors.lastname: Bui
authors.affiliation: Department of Biology, California State University Northridge, Northridge, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kelber
authors.affiliation: Department of Surgery, University of California, San Diego, La Jolla, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.|Department of Pharmacology, University of California, San Diego, La Jolla, California.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California. rklemke@ucsd.edu.|Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Klemke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010448:Peptide Initiation Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D050814:Octamer Transcription Factor-3; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C494173:POU5F1 protein, human; C551991:WWTR1 protein, human; C088374:YAP1 protein, human; C573947:PEAK1 protein, human