PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma

PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
Title:
PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
Other Titles:
Journal of Experimental Medicine
Keywords:
Publication Date:
21 March 2019
Citation:
Yong Jae Shin, Jason K. Sa, Yeri Lee, Donggeon Kim, Nakho Chang, Hee Jin Cho, Miseol Son, Michael Y.T. Oh, Kayoung Shin, Jin-Ku Lee, Jiwon Park, Yoon Kyung Jo, Misuk Kim, Patrick J. Paddison, Vinay Tergaonkar, Jeongwu Lee, Do-Hyun Nam; PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma. J Exp Med 6 May 2019; 216 (5): 1120–1134. doi: https://doi.org/10.1084/jem.20172170
Abstract:
Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This research was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418). Additional support was from National Institutes of Health grants R01 NS082312, R56 NS095822, R01 CA223370 (J. Lee), and R01 CA190957 (P.J. Paddison).
Description:
ISSN:
0022-1007
1540-9538
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