Morin‐dependent inhibition of low molecular weight protein tyrosine phosphatase (LMW‐PTP) restores sensitivity to apoptosis during colon carcinogenesis: Studies in vitro and in vivo, in anApc‐driven model of colon cancer

ABSTRACT The low-molecular-weight protein tyrosine phosphatase (LMWPTPase) belongs to a distinctive class of phosphotyrosine phosphatases widely distributed among prokaryotes and eukaryotes. We report here the crystal structure of LMWPTPase of microbial origin, the first of its kind from Mycobacterium tuberculosis. The structure was determined to be two crystal forms at 1.9- and 2.5-Å resolutions. These structural forms are compared with those of the LMWPTPases of eukaryotes. Though the overall structure resembles that of the eukaryotic LMWPTPases, there are significant changes around the active site and the protein tyrosine phosphatase (PTP) loop. The variable loop forming the wall of the crevice leading to the active site is conformationally unchanged from that of mammalian LMWPTPase; however, differences are observed in the residues involved, suggesting that they have a role in influencing different substrate specificities. The single amino acid substitution (Leu12Thr [underlined below]) in the consensus sequence of the PTP loop, C T GNICRS, has a major role in the stabilization of the PTP loop, unlike what occurs in mammalian LMWPTPases. A chloride ion and a glycerol molecule were modeled in the active site where the chloride ion interacts in a manner similar to that of phosphate with the main chain nitrogens of the PTP loop. This structural study, in addition to identifying specific mycobacterial features, may also form the basis for exploring the mechanism of the substrate specificities of bacterial LMWPTPases.

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Kinetic Characterization of Bovine Lung Low-Molecular-Weight Protein Tyrosine Phosphatase

Experimental Lung Research ◽

10.3109/01902149809041534 ◽

1998 ◽

Vol 24 (3) ◽

pp. 269-272 ◽

Cited By ~ 6

Author(s):

Marilia A. R. Buzalaf ◽

E. M. Taga ◽

JosÉ M. Granjeiro ◽

Carmen V. Ferreira ◽

ValÉRia A. Lourençā ◽

...

Keyword(s):

Molecular Weight ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Low Molecular Weight ◽

Kinetic Characterization ◽

Molecular Weight Protein ◽

Protein Tyrosine ◽

Weight Protein ◽

Low Molecular Weight Protein

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Structure-based discovery of new small molecule inhibitors of low molecular weight protein tyrosine phosphatase

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2007.01.017 ◽

2007 ◽

Vol 42 (8) ◽

pp. 1102-1108 ◽

Cited By ~ 18

Author(s):

David Vidal ◽

Jascha Blobel ◽

Yolanda Pérez ◽

Michael Thormann ◽

Miquel Pons

Keyword(s):

Molecular Weight ◽

Small Molecule ◽

Protein Tyrosine Phosphatase ◽

Small Molecule Inhibitors ◽

Tyrosine Phosphatase ◽

Low Molecular Weight ◽

Molecular Weight Protein ◽

Protein Tyrosine ◽

Weight Protein ◽

Low Molecular Weight Protein

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The usefullness of low-molecular-weight protein tyrosine phosphatase as a prognostic factor in metastatic hormone-sensitive prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.277 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 277-277

Author(s):

Mari Ohtaka ◽

Takashi Kawahara ◽

Masato Yasui ◽

Kouichi Uemura ◽

Shuko Yoneyama ◽

...

Keyword(s):

Prostate Cancer ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Low Molecular Weight ◽

Protein Tyrosine Phosphorylation ◽

Molecular Weight Protein ◽

Protein Tyrosine ◽

Weight Protein ◽

Hormone Sensitive ◽

Low Molecular Weight Protein

277 Background: Protein tyrosine phosphorylation is an important event that is associated with the processes of cellular metabolism. The control of protein tyrosine phosphorylation is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTP). Thus, these proteins can control diverse processes like cell proliferation, adhesion, and migration. Recent studies revealed the importance of PTP in the oncogenic process, especially, the significance of low-molecular-weight protein tyrosine phosphatase (LMW-PTP) as a prognostic factor in early prostate cancer. In this study, we evaluated the significance of expression of LMW-PTP in metastatic hormone-sensitive prostate cancer (mHSPC) as a prognostic biomarker. Methods: We identified consecutive 48 men with mHSPC. The prostate cancer tissues obtained by needle biopsies were immunohistochemically stained for LMW-PTP. A pathologist blindly evaluated the expression of LMW-PTP and intensity of staining was classified into two groups, high (diffusely strongly positive) and low (at least focally weak-negative). The correlations between clinicopathological characteristics including age, initial PSA levels, Gleason scores, T stage, N stage, extend of disease on bone scan (EOD), and expression of LMW-PTP and overall survival (OS) were analyzed by multivariate analysis using cox proportional hazards regression model. Results: Median age was 70.0 years and median initial PSA level was 85.4 ng/mL. Gleason scores were 6-7 in 16 patients (33.4%) and 8-10 in 32 patients (66.6%). Clinical T stages were T2-3 disease in 34 patients (70.8%) and T4 in 14 patients (29.2%). Clinical N stages were N0 disease in 21 patients (43.7%) and N1 in 27 patients (56.3%). EOD grades were 0 in 13 patients (27.0%), 1 in 12 patients (25.0%), 2 in 14 patients (29.2%), 3 in 8 patients (16.7%), and 4 in 1 patient (2.1%). Multivariate analysis revealed that Gleason score (≥ 8 vs ≤ 7; HR: 5.795, 95%CI: 1.266-26.520, p = 0.024) and LMW-PTP expression (high vs low; HR: 2.736, 95%CI: 1.035-7.232, p = 0.042) were independent prognostic factors for OS. Conclusions: LMW-PTP might be a potential biomarker to predict overall survival for men with mHSPC.

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