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The Role of Phosphatases in Human Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 9126

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Dr. Hussain Raza

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Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju 32588, Korea
Interests: enzyme inhibition; drug testing; antioxidant; molecular docking
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Dear Colleagues,

Phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Phosphatase enzymes catalyze the hydrolysis of their substrates, making them subcategories of hydrolases. In cellular regulation and signalling, phosphatases and protein kinases play essential roles in phosphorylation and dephosphorylation (e.g., protein kinases). Phosphatases play an important role in a range of human diseases, including cancer, cardiovascular, metabolic and neurological disorders. Intestinal alkaline phosphatase (ALP) is the main enzyme linked to phosphatase. Based on the tissues in which it is expressed, there are four isozymes: intestinal alkaline phosphatase, placental alkaline phosphatase, germ cell alkaline phosphatase, and liver/bone/kidney alkaline phosphatase. The low levels of this enzyme can suggest zinc, magnesium, or protein deficiency. People who consistently take high vitamin D doses or certain medications are also more likely to have low levels of this enzyme. In addition to these causes, an underactive thyroid, anemia, and genetic conditions may also be responsible.

The Special Issue, “The Role of Phosphatases in Human Health and Disease” will cover recent research on the phosphatase and their types which play an important role in our health, also the novel compounds which can be used to treat this disease which occur due to the lack of this enzyme in the human body. Research articles/reviews related to this disease and enzymes are welcome in this issue.

You may choose our Joint Special Issue in Kinases and Phosphatases.

Dr. Hussain Raza
Guest Editor

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Keywords

enzymes
phosphatase
diseases
free radicals
synthesis
docking
pharmacology
animals

Published Papers (7 papers)

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Research

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17 pages, 6963 KiB

Open AccessArticle

Identification of PTPN12 Phosphatase as a Novel Negative Regulator of Hippo Pathway Effectors YAP/TAZ in Breast Cancer

by Sahar Sarmasti Emami, Anni Ge, Derek Zhang, Yawei Hao, Min Ling, Rachel Rubino, Christopher J. B. Nicol, Wenqi Wang and Xiaolong Yang

Int. J. Mol. Sci. 2024, 25(7), 4064; https://doi.org/10.3390/ijms25074064 - 05 Apr 2024

Viewed by 544

Abstract

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, that subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer biology and potential therapeutic strategies. Full article

(This article belongs to the Special Issue The Role of Phosphatases in Human Health and Disease)

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15 pages, 3598 KiB

Open AccessArticle

PTPN13 Participates in the Regulation of Epithelial–Mesenchymal Transition and Platinum Sensitivity in High-Grade Serous Ovarian Carcinoma Cells

by Leticia Aptecar, Carole Puech, Evelyne Lopez-Crapez, Marion Peter, Peter Coopman, Véronique D’Hondt and Gilles Freiss

Int. J. Mol. Sci. 2023, 24(20), 15413; https://doi.org/10.3390/ijms242015413 - 21 Oct 2023

Cited by 2 | Viewed by 1284

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological cancers in Western countries. High-Grade Serous Ovarian Carcinoma (HGSOC) accounts for 60–70% of EOC and is the most aggressive subtype. Reduced PTPN13 expression levels have been previously correlated with worse prognosis in HGSOC. However, PTPN13’s exact role and mechanism of action in these tumors remained to be investigated. To elucidate PTPN13’s role in HGSOC aggressiveness, we used isogenic PTPN13-overexpressing clones of the OVCAR-8 cell line, which poorly expresses PTPN13, and also PTPN13 CRISPR/Cas9-mediated knockout/knockdown clones of the KURAMOCHI cell line, which strongly expresses PTPN13. We investigated their migratory and invasive capacity using a wound healing assay, their mesenchymal-epithelial transition (EMT) status using microscopy and RT-qPCR, and their sensitivity to chemotherapeutic drugs used for HGSOC. We found that (i) PTPN13 knockout/knockdown increased migration and invasion in KURAMOCHI cells that also displayed a more mesenchymal phenotype and increased expression of the SLUG, SNAIL, ZEB-1, and ZEB-2 EMT master genes; and (ii) PTPN13 expression increased the platinum sensitivity of HGSOC cells. These results suggest that PTPN13 might be a predictive marker of response to platinum salts in HGSOC. Full article

(This article belongs to the Special Issue The Role of Phosphatases in Human Health and Disease)

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11 pages, 1095 KiB

Open AccessArticle

Increased Drop in Activity of Alkaline Phosphatase in Plasma from Patients with Endocarditis

by Amila Kahrovic, Thomas Poschner, Anna Schober, Philipp Angleitner, Leila Alajbegovic, Martin Andreas, Doris Hutschala, Ruud Brands, Günther Laufer and Dominik Wiedemann

Int. J. Mol. Sci. 2023, 24(14), 11728; https://doi.org/10.3390/ijms241411728 - 21 Jul 2023

Viewed by 760

Abstract

(1) Infective endocarditis is a severe inflammatory disease associated with substantial mortality and morbidity. Alkaline phosphatase (AP) levels have been shown to change significantly during sepsis. Additionally, we previously found that a higher initial AP drop after cardiac surgery is associated with unfavorable outcomes. Therefore, the course of AP after surgery for endocarditis is of special interest. (2) A total of 314 patients with active isolated left-sided infective endocarditis at the Department of Cardiac Surgery (Medical University of Vienna, Vienna, Austria) between 2009 and 2018 were enrolled in this retrospective analysis. Blood samples were analyzed at different time points (baseline, postoperative days 1–7, postoperative days 14 and 30). Patients were categorized according to relative alkaline phosphatase drop (≥30% vs. <30%). (3) A higher rate of postoperative renal replacement therapy with or without prior renal replacement therapy (7.4 vs. 21.8%; p = 0.001 and 6.7 vs. 15.6%; p = 0.015, respectively) and extracorporeal membrane oxygenation (2.2 vs. 19.0%; p = 0.000) was observed after a higher initial alkaline phosphatase drop. Short-term (30-day mortality 3.0 vs. 10.6%; p = 0.010) and long-term mortality (p = 0.008) were significantly impaired after a higher initial alkaline phosphatase drop. (4) The higher initial alkaline phosphatase drop was accompanied by impaired short- and long-term outcomes after cardiac surgery for endocarditis. Future risk assessment scores for cardiac surgery should consider alkaline phosphatase. Full article

(This article belongs to the Special Issue The Role of Phosphatases in Human Health and Disease)

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23 pages, 4079 KiB

Open AccessArticle

Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies

by Narges Hosseini Nasab, Hussain Raza, Rok Su Shim, Mubashir Hassan, Andrzej Kloczkowski and Song Ja Kim

Int. J. Mol. Sci. 2022, 23(21), 13262; https://doi.org/10.3390/ijms232113262 - 31 Oct 2022

Cited by 6 | Viewed by 1866

Abstract

To develop new alkaline phosphatase inhibitors (ALP), a series of pyrazolo-oxothiazolidine derivatives were synthesized and biologically assessed, and the results showed that all of the synthesized compounds significantly inhibited ALP. Specifically, compound 7g displayed the strongest inhibitory activity (IC₅₀ = 0.045 ± 0.004 μM), which is 116-fold more active than monopotassium phosphate (IC₅₀ = 5.242 ± 0.472 μM) as a standard reference. The most potent compound among the series (7g) was checked for its mode of binding with the enzyme and shown as non-competitively binding with the target enzyme. The antioxidant activity of these compounds was examined to investigate the radical scavenging effect. Moreover, the MTT assay method was performed to evaluate their toxic effects on the viability of MG-63 human osteosarcoma cells, and all compounds have no toxic effect on the cells at 4 μM. Computational research was also conducted to examine the binding affinity of the ligands with alkaline phosphatase, and the results revealed that all compounds showed good binding energy values within the active site of the target. Therefore, these novel pyrazolo-oxothiazolidine derivatives might be employed as promising pharmacophores for potent and selective alkaline phosphatase inhibitors. Full article

(This article belongs to the Special Issue The Role of Phosphatases in Human Health and Disease)

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15 pages, 4222 KiB

Open AccessReview

Analysis of Receptor-Type Protein Tyrosine Phosphatase Extracellular Regions with Insights from AlphaFold

by Lina El Badaoui and Alastair J. Barr

Int. J. Mol. Sci. 2024, 25(2), 820; https://doi.org/10.3390/ijms25020820 - 09 Jan 2024

Viewed by 759

Abstract

The receptor-type protein tyrosine phosphatases (RPTPs) are involved in a wide variety of physiological functions which are mediated via their diverse extracellular regions. They play key roles in cell–cell contacts, bind various ligands and are regulated by dimerization and other processes. Depending on the subgroup, they have been described as everything from ‘rigid rods’ to ‘floppy tentacles’. Here, we review current experimental structural knowledge on the extracellular region of RPTPs and draw on AlphaFold structural predictions to provide further insights into structure and function of these cellular signalling molecules, which are often mutated in disease and are recognised as drug targets. In agreement with experimental data, AlphaFold predicted structures for extracellular regions of R1, and R2B subgroup RPTPs have an extended conformation, whereas R2B RPTPs are twisted, reflecting their high flexibility. For the R3 PTPs, AlphaFold predicts that members of this subgroup adopt an extended conformation while others are twisted, and that certain members, such as CD148, have one or more large, disordered loop regions in place of fibronectin type 3 domains suggested by sequence analysis. Full article

(This article belongs to the Special Issue The Role of Phosphatases in Human Health and Disease)

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27 pages, 1132 KiB

Open AccessReview

Maintaining Genome Integrity: Protein Kinases and Phosphatases Orchestrate the Balancing Act of DNA Double-Strand Breaks Repair in Cancer

by Sisi Qin, Ichiwa Kitty, Yalan Hao, Fei Zhao and Wootae Kim

Int. J. Mol. Sci. 2023, 24(12), 10212; https://doi.org/10.3390/ijms241210212 - 16 Jun 2023

Cited by 3 | Viewed by 1369

Abstract

DNA double-strand breaks (DSBs) are the most lethal DNA damages which lead to severe genome instability. Phosphorylation is one of the most important protein post-translation modifications involved in DSBs repair regulation. Kinases and phosphatases play coordinating roles in DSB repair by phosphorylating and dephosphorylating various proteins. Recent research has shed light on the importance of maintaining a balance between kinase and phosphatase activities in DSB repair. The interplay between kinases and phosphatases plays an important role in regulating DNA-repair processes, and alterations in their activity can lead to genomic instability and disease. Therefore, study on the function of kinases and phosphatases in DSBs repair is essential for understanding their roles in cancer development and therapeutics. In this review, we summarize the current knowledge of kinases and phosphatases in DSBs repair regulation and highlight the advancements in the development of cancer therapies targeting kinases or phosphatases in DSBs repair pathways. In conclusion, understanding the balance of kinase and phosphatase activities in DSBs repair provides opportunities for the development of novel cancer therapeutics. Full article

(This article belongs to the Special Issue The Role of Phosphatases in Human Health and Disease)

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25 pages, 1198 KiB

Open AccessReview

Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine

by Rosanna Maccari and Rosaria Ottanà

Int. J. Mol. Sci. 2023, 24(11), 9621; https://doi.org/10.3390/ijms24119621 - 01 Jun 2023

Cited by 3 | Viewed by 1772

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure–activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors. Full article

(This article belongs to the Special Issue The Role of Phosphatases in Human Health and Disease)

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