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Ubiquitin‐binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer
Author(s) -
Xiong Xunhao,
Rao Geeta,
Roy Ram Vinod,
Zhang Yushan,
Means Nicolas,
Dey Anindya,
Tsaliki Martha,
Saha Sounik,
Bhattacharyya Sanjib,
Dhar Dwivedi Shailendra Kumar,
Rao Chinthalapally V.,
McCormick Daniel J.,
Dhanasekaran Danny,
Ding Kai,
Gillies Elizabeth,
Zhang Min,
Yang Da,
Bhattacharya Resham,
Mukherjee Priyabrata
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902826rr
Subject(s) - kras , pancreatic cancer , cancer research , pinocytosis , gene silencing , cancer , cancer cell , chemistry , microbiology and biotechnology , biology , cell , endocytosis , biochemistry , colorectal cancer , gene , genetics
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.