Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3

Shuping Yang, Lin Zhang, Vinee Purohit, Surendra K. Shukla, Xingcheng Chen, Fang Yu, Kai Fu, Yuanhong Chen, Joyce Solheim, Pankaj K. Singh, Wei Song, Jixin Dong

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)36019-36031
Number of pages13
JournalOncotarget
Volume6
Issue number34
DOIs
StatePublished - Jan 1 2015

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Keywords

  • Cell motility
  • Hippo-YAP pathway
  • LPAR3
  • Mitotic phosphorylation
  • PDAC

ASJC Scopus subject areas

  • Oncology

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