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Mol Cell. 2014 Mar 6;53(5):752-65. doi: 10.1016/j.molcel.2014.01.020. Epub 2014 Feb 13.

GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis.

Author information

1
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China.
2
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China; Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Beijing Key Lab, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
4
Departments of General Surgery and Pathology, Chinese PLA General Hospital, Beijing 100853, China.
5
Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
6
Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease and Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong, China.
7
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
8
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China.
9
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
10
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Electronic address: yechin@sibs.ac.cn.
11
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: zhijiec@tsinghua.edu.cn.

Abstract

Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of TC-PTP) and STAT3 specifically. GdX stabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficient dephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX converts TC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.

PMID:
24530303
DOI:
10.1016/j.molcel.2014.01.020
[Indexed for MEDLINE]
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