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

Authors :
Xiong X
Rao G
Roy RV
Zhang Y
Means N
Dey A
Tsaliki M
Saha S
Bhattacharyya S
Dhar Dwivedi SK
Rao CV
McCormick DJ
Dhanasekaran D
Ding K
Gillies E
Zhang M
Yang D
Bhattacharya R
Mukherjee P
Source :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Sep; Vol. 34 (9), pp. 12024-12039. Date of Electronic Publication: 2020 Jul 21.
Publication Year :
2020

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.<br /> (© 2020 Federation of American Societies for Experimental Biology.)

Details

Language :
English
ISSN :
1530-6860
Volume :
34
Issue :
9
Database :
MEDLINE
Journal :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Publication Type :
Academic Journal
Accession number :
32692445
Full Text :
https://doi.org/10.1096/fj.201902826RR