title: Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3.
abstract: The transcriptional co-activator Yes-associated protein, YAP, is a main effector in the Hippo tumor suppressor pathway. We recently defined a mechanism for positive regulation of YAP through CDK1-mediated mitotic phosphorylation. Here, we show that active YAP promotes pancreatic cancer cell migration, invasion and anchorage-independent growth in a mitotic phosphorylation-dependent manner. Mitotic phosphorylation is essential for YAP-driven tumorigenesis in animals. YAP reduction significantly impairs cell migration and invasion. Immunohistochemistry shows significant upregulation and nuclear localization of YAP in metastases when compared with primary tumors and normal tissue in human. Mitotic phosphorylation of YAP controls a unique transcriptional program in pancreatic cells. Expression profiles reveal LPAR3 (lysophosphatidic acid receptor 3) as a mediator for mitotic phosphorylation-driven pancreatic cell motility and invasion. Together, this work identifies YAP as a novel regulator of pancreatic cancer cell motility, invasion and metastasis, and as a potential therapeutic target for invasive pancreatic cancer.
authors.affiliation: Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong, P. R. China.|Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China.|Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Vinee
authors.initials: V
authors.lastname: Purohit
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Shukla
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Xingcheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, School of Public Health, Omaha, NE, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Solheim
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
authors.forename: Jixin
authors.initials: J
authors.lastname: Dong
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D049368:Receptors, Lysophosphatidic Acid; D014157:Transcription Factors; C456659:YY1AP1 protein, human
keywords: Hippo-YAP pathway; LPAR3; PDAC; cell motility; mitotic phosphorylation