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Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma.

ABSTRACT: Protein tyrosine phosphatase 1B (PTP1B) is known to promote the pathogenesis of diabetes and obesity by negatively regulating insulin and leptin pathways, but its role associated with colon carcinogenesis is still under debate. In this study, we demonstrated the oncogenic role of PTP1B in promoting colon carcinogenesis and predicting worse clinical outcomes in CRC patients. By co-immunoprecipitation, we showed that PITX1 was a novel substrate of PTP1B. Through direct dephosphorylation at Y160, Y175 and Y179, PTP1B destabilized PITX1, which resulted in downregulation of the PITX1/p120RasGAP axis. Interestingly, we found that regorafenib, the approved target agent for advanced CRC patients, exerted a novel property against PTP1B. By inhibiting PTP1B activity, regorafenib treatment augmented the stability of PITX1 protein and upregulated the expression of p120RasGAP in CRC. Importantly, we found that this PTP1B-dependant PITX1/p120RasGAP axis determines the in vitro anti-CRC effects of regorafenib. The above-mentioned effects of regorafenib were confirmed by the HT-29 xenograft tumor model. In conclusion, we demonstrated a novel oncogenic mechanism of PTP1B on affecting PITX1/p120RasGAP in CRC. Regorafenib inhibited CRC survival through reserving PTP1B-dependant PITX1/p120RasGAP downregulation. PTP1B may be a potential biomarker predicting regorafenib effectiveness, and a potential solution for CRC.

SUBMITTER: Teng HW

PROVIDER: S-EPMC5082755 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma.

Teng Hao-Wei HW Hung Man-Hsin MH Chen Li-Ju LJ Chang Mao-Ju MJ Hsieh Feng-Shu FS Tsai Ming-Hsien MH Huang Jui-Wen JW Lin Chih-Lung CL Tseng Hsiang-Wen HW Kuo Zong-Keng ZK Jiang Jeng-Kai JK Yang Shung-Haur SH Shiau Chung-Wai CW Chen Kuen-Feng KF

Scientific reports 20161018

Protein tyrosine phosphatase 1B (PTP1B) is known to promote the pathogenesis of diabetes and obesity by negatively regulating insulin and leptin pathways, but its role associated with colon carcinogenesis is still under debate. In this study, we demonstrated the oncogenic role of PTP1B in promoting colon carcinogenesis and predicting worse clinical outcomes in CRC patients. By co-immunoprecipitation, we showed that PITX1 was a novel substrate of PTP1B. Through direct dephosphorylation at Y160, Y ...[more]

PMID: 27752061

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Project description:A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn2+) inhibit with picomolar to nanomolar affinities. We mapped the cation binding site close to the anion binding site and established a specific mechanism of inhibition occurring only in the closed conformation of the enzyme when the catalytic cysteine is phosphorylated and the catalytic aspartate moves into the active site. We discuss this dual inhibition by anions and cations here for PTP1B, the most thoroughly investigated protein tyrosine phosphatase. The significance of the inhibition in phosphorylation signaling is becoming apparent only from the functions of PTP1B in the biological context of metal cations as cellular signaling ions. Zinc ion signals complement redox signals but provide a different type of control and longer lasting inhibition on a biological time scale owing to the specificity and affinity of zinc ions for coordination environments. Inhibitor design for PTP1B and other PTPs is a major area of research activity and interest owing to their prominent roles in metabolic regulation in health and disease, in particular cancer and diabetes. Our results explain the apparent dichotomy of both cations (Zn2+) and oxyanions such as vanadate inhibiting PTP1B and having insulin-enhancing ("anti-diabetic") effects and suggest different approaches, namely targeting PTPs in the cell by affecting their physiological modulators and considering a metallodrug approach that builds on the knowledge of the insulin-enhancing effects of both zinc and vanadium compounds.

Project description:Because of their antagonistic catalytic functions, protein-tyrosine phosphatases (PTPs) and protein-tyrosine kinases act together to control phosphotyrosine-mediated signaling processes in mammalian cells. However, unlike for protein-tyrosine kinases, little is known about the cellular substrate specificity of many PTPs because of the lack of appropriate methods for the systematic and detailed analysis of cellular PTP function. Even for the most intensely studied, prototypic family member PTP1B many of its physiological functions cannot be explained by its known substrates. To gain better insights into cellular PTP1B function, we used quantitative MS to monitor alterations in the global tyrosine phosphorylation of PTP1B-deficient mouse embryonic fibroblasts in comparison with their wild-type counterparts. In total, we quantified 124 proteins containing 301 phosphotyrosine sites under basal, epidermal growth factor-, or platelet-derived growth factor-stimulated conditions. A subset of 18 proteins was found to harbor hyperphosphorylated phosphotyrosine sites in knock-out cells and was functionally linked to PTP1B. Among these proteins, regulators of cell motility and adhesion are overrepresented, such as cortactin, lipoma-preferred partner, ZO-1, or p120ctn. In addition, regulators of proliferation like p62DOK or p120RasGAP also showed increased cellular tyrosine phosphorylation. Physical interactions of these proteins with PTP1B were further demonstrated by using phosphatase-inactive substrate-trapping mutants in a parallel MS-based analysis. Our results correlate well with the described phenotype of PTP1B-deficient fibroblasts that is characterized by an increase in motility and reduced cell proliferation. The presented study provides a broad overview about phosphotyrosine signaling processes in mouse fibroblasts and, supported by the identification of various new potential substrate proteins, indicates a central role of PTP1B within cellular signaling networks. Importantly the MS-based strategies described here are entirely generic and can be used to address the poorly understood aspects of cellular PTP function.

Dataset Information

Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma.

Publications

Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma.

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