Abstract 2379: PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function

Abstract

Abstract Department of Genetics & Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA. In addition to phosphorylation, tyrosine residues in proteins can have nitration at the 3-carbon position on the phenol ring (Y-NO2). Protein tyrosine nitration occurs under both physiological and pathologic conditions. However, enzymes that add or remove this protein modification remain to be identified. Protein tyrosine phosphatase receptor T (PTPRT) is one of the twelve receptor protein tyrosine phosphatases (RPTPs) that have two catalytic PTP domains in their intracellular parts. While the membrane proximal PTP domains (D1) are protein tyrosine phosphatases, it has been thought that the C-terminal PTP domains (D2) are pseudo-phosphatase that lack enzymatic activity. Here we report that the pseudo-phosphatase domain (D2) of PTPRT is a denitrase that removes nitro-groups from tyrosine residues in paxillin. PTPRT normally functions as a tumor suppressor and is frequently mutated in a variety of human cancers including colorectal cancer. Interestingly, a fifth of tumor-derived mutations of PTPRT are located in the D2 pseudo-PTP domain. We demonstrate that some of the tumor-derived mutations located in the pseudo-phosphatase domain impair the denitrase activity. Moreover, PTPRT mutant mice that inactivate the denitrase activity are susceptible to carcinogen-induced colon tumor formation. Our study uncovers a novel enzyme that functions as a tumor suppressor. Citation Format: Yiqing Zhao, Zhenghe Wang. PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2379.