Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3
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Shuping Yang1,3,*, Lin Zhang2,3,*, Vinee Purohit3, Surendra K. Shukla3, Xingcheng Chen3, Fang Yu4, Kai Fu5, Yuanhong Chen3, Joyce Solheim3, Pankaj K. Singh3, Wei Song1 and Jixin Dong3
1 Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong, P. R. China
2 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China
3 Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center, Omaha, NE, USA
4 Department of Biostatistics, School of Public Health, Omaha, NE, USA
5 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
* These authors have contributed equally to this work
Jixin Dong, email:
Keywords: Hippo-YAP pathway, PDAC, cell motility, LPAR3, mitotic phosphorylation
Received: August 06, 2015 Accepted: September 14, 2015 Published: September 30, 2015
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.
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