Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer

Xunhao Xiong, Geeta Rao, Ram Vinod Roy, Yushan Zhang, Nicolas Means, Anindya Dey, Martha Tsaliki, Sounik Saha, Sanjib Bhattacharyya, Shailendra Kumar Dhar Dwivedi, Chinthalapally V. Rao, Daniel J. McCormick, Danny Dhanasekaran, Kai Ding, Elizabeth Gillies, Min Zhang, Da Yang, Resham Bhattacharya, Priyabrata Mukherjee

Research output: Contribution to journalArticlepeer-review

Abstract

Macropinocytosis supports the metabolic requirement of RAS-transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS-transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin-binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2-deletion construct, we demonstrate that the UBA-domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP-bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS-driven cancers.

Original languageEnglish (US)
Pages (from-to)12024-12039
Number of pages16
JournalFASEB Journal
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2020

Keywords

  • KRAS
  • UBAP2
  • macropinocytosis
  • pancreatic cancer
  • small GTPases
  • therapeutic target

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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