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Biochimica Et Biophysica Acta.... Jan 2019Myosin phosphatase (MP) holoenzyme is a Ser/Thr specific enzyme, which is the member of protein phosphatase type 1 (PP1) family and composed of a PP1 catalytic subunit... (Review)
Review
Myosin phosphatase (MP) holoenzyme is a Ser/Thr specific enzyme, which is the member of protein phosphatase type 1 (PP1) family and composed of a PP1 catalytic subunit (PP1c/PPP1CB) and a myosin phosphatase targeting subunit (MYPT1/PPP1R12A). PP1c is required for the catalytic activity of the holoenzyme, while MYPT1 regulates MP through targeting the holoenzyme to its substrates. Above the well-characterized function of MP, as the major regulator of smooth muscle contractility mediating the dephosphorylation of 20 kDa myosin light chain, accumulating data support its role in other, non-contractile functions. In this review, we summarize the scaffold function of MP holoenzyme and its roles in processes such as cell cycle, development, gene expression regulation and neurotransmitter release. In particular, we highlight novel interacting proteins of MYPT1 and pathophysiological functions of MP relevant to tumorigenesis, insulin resistance and neurodegenerative disorders. This article is part of a Special Issue entitled: Protein Phosphatases as Critical Regulators for Cellular Homeostasis edited by Prof. Peter Ruvolo and Dr. Veerle Janssens.
Topics: Animals; Humans; Insulin Resistance; Myocytes, Smooth Muscle; Myosin-Light-Chain Phosphatase; Neoplasms; Neurofibromin 2; Phosphoprotein Phosphatases; Protein Phosphatase 1
PubMed: 30076859
DOI: 10.1016/j.bbamcr.2018.07.023 -
Journal of Cell Science Oct 2022Protein phosphorylation on serine and threonine residues is a widely distributed post-translational modification on proteins that acts to regulate their function.... (Review)
Review
Protein phosphorylation on serine and threonine residues is a widely distributed post-translational modification on proteins that acts to regulate their function. Phosphoprotein phosphatases (PPPs) contribute significantly to a plethora of cellular functions through the accurate dephosphorylation of phosphorylated residues. Most PPPs accomplish their purpose through the formation of complex holoenzymes composed of a catalytic subunit with various regulatory subunits. PPP holoenzymes then bind and dephosphorylate substrates in a highly specific manner. Despite the high prevalence of PPPs and their important role for cellular function, their mechanisms of action in the cell are still not well understood. Nevertheless, substantial experimental advancements in (phospho-)proteomics, structural and computational biology have contributed significantly to a better understanding of PPP biology in recent years. This Review focuses on recent approaches and provides an overview of substantial new insights into the complex mechanism of PPP holoenzyme regulation and substrate selectivity.
Topics: Holoenzymes; Phosphoprotein Phosphatases; Phosphoproteins; Phosphorylation; Protein Phosphatase 2; Serine; Threonine
PubMed: 36205606
DOI: 10.1242/jcs.259618 -
Oncogene Aug 2015Understanding the factors contributing to tumor initiation, progression and evolution is of paramount significance. Among them, wild-type p53-induced phosphatase 1... (Review)
Review
Understanding the factors contributing to tumor initiation, progression and evolution is of paramount significance. Among them, wild-type p53-induced phosphatase 1 (Wip1) is emerging as an important oncogene by virtue of its negative control on several key tumor suppressor pathways. Originally discovered as a p53-regulated gene, Wip1 has been subsequently found amplified and more recently mutated in a significant fraction of human cancers including breast tumors. Recent development in the field further uncovered the utility of anti-Wip1-directed therapies in delaying tumor onset or in reducing the tumor burden. Furthermore, Wip1 could be an important factor that contributes to tumor heterogeneity, suggesting that its inhibition may decrease the rate of cancer evolution. These effects depend on several signaling pathways modulated by Wip1 phosphatase in a spatial and temporal manner. In this review we discuss the recent development in understanding how Wip1 contributes to tumorigenesis with its relevance to breast cancer.
Topics: Breast; Breast Neoplasms; Cytidine Deaminase; DNA Damage; Female; Genes, BRCA2; Genes, p53; Heterochromatin; Humans; Minor Histocompatibility Antigens; Mutation; Oncogenes; Phosphoprotein Phosphatases; Protein Phosphatase 2C; Receptor, ErbB-2; Wnt1 Protein
PubMed: 25381821
DOI: 10.1038/onc.2014.375 -
The Journal of Biological Chemistry Jul 2021More than half a century ago, reversible protein phosphorylation was linked to mitochondrial metabolism through the regulation of pyruvate dehydrogenase. Since this... (Review)
Review
More than half a century ago, reversible protein phosphorylation was linked to mitochondrial metabolism through the regulation of pyruvate dehydrogenase. Since this discovery, the number of identified mitochondrial protein phosphorylation sites has increased by orders of magnitude, driven largely by technological advances in mass spectrometry-based phosphoproteomics. However, the majority of these modifications remain uncharacterized, rendering their function and relevance unclear. Nonetheless, recent studies have shown that disruption of resident mitochondrial protein phosphatases causes substantial metabolic dysfunction across organisms, suggesting that proper management of mitochondrial phosphorylation is vital for organellar and organismal homeostasis. While these data suggest that phosphorylation within mitochondria is of critical importance, significant gaps remain in our knowledge of how these modifications influence organellar function. Here, we curate publicly available datasets to map the extent of protein phosphorylation within mammalian mitochondria and to highlight the known functions of mitochondrial-resident phosphatases. We further propose models by which phosphorylation may affect mitochondrial enzyme activities, protein import and processing, and overall organellar homeostasis.
Topics: Animals; Humans; Mitochondrial Proteins; Phosphoprotein Phosphatases; Phosphoproteins; Phosphorylation; Protein Kinases; Proteome
PubMed: 34144036
DOI: 10.1016/j.jbc.2021.100880 -
European Journal of Medicinal Chemistry Jan 2024Phosphatase is a kind of enzyme that can dephosphorylate target proteins, which can be divided into serine/threonine phosphatase and tyrosine phosphatase according to... (Review)
Review
Phosphatase is a kind of enzyme that can dephosphorylate target proteins, which can be divided into serine/threonine phosphatase and tyrosine phosphatase according to its mode of action. Current evidence showed multiple phosphatases were highly correlated with diseases including various cancers, demonstrating them as potential targets. However, currently, targeting phosphatases with small molecules faces many challenges, resulting in no drug approved. In this case, phosphatases are even regarded as "undruggable" targets for a long time. Recently, a variety of strategies have been adopted in the design of small molecule inhibitors targeting phosphatases, leading many of them to enter into the clinical trials. In this review, we classified these inhibitors into 4 types, including (1) molecular glues, (2) small molecules targeting catalytic sites, (3) allosteric inhibition, and (4) bifunctional molecules (proteolysis targeting chimeras, PROTACs). These molecules with diverse strategies prove the feasibility of phosphatases as drug targets. In addition, the combination therapy of phosphatase inhibitors with other drugs has also entered clinical trials, which suggests a broad prospect. Thus, targeting phosphatases with small molecules by different strategies is emerging as a promising way in the modulation of pathogenetic phosphorylation.
Topics: Humans; Phosphoprotein Phosphatases; Protein Tyrosine Phosphatases; Enzyme Inhibitors; Phosphorylation; Neoplasms; Proteolysis
PubMed: 38101039
DOI: 10.1016/j.ejmech.2023.116031 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2018Protein phosphatases, while long overlooked, have recently become appreciated as drivers of both normal- and disease-associated signaling events. As a result, the... (Review)
Review
Protein phosphatases, while long overlooked, have recently become appreciated as drivers of both normal- and disease-associated signaling events. As a result, the spotlight is now turning torwards this enzyme family and efforts geared towards the development of modern chemical tools for studying these enzymes are well underway. This Minireview focuses on the evolution of chemical activity probes, both optical and covalent, for the study of protein phosphatases. Small-molecule probes, global monitoring of phosphatase activity through the use of covalent modifiers, and targeted fluorescence-based activity probes are discussed. We conclude with an overview of open questions in the field and highlight the potential impact of chemical tools for studying protein phosphatases.
Topics: Animals; Biomarkers; Fluorescent Dyes; Humans; Kinetics; Phosphoprotein Phosphatases; Signal Transduction
PubMed: 29338103
DOI: 10.1002/chem.201705194 -
Biochimica Et Biophysica Acta.... Jan 2019Protein synthesis is one of the most complex and energy-consuming processes in eukaryotic cells and therefore is tightly regulated. One of the main mechanisms of... (Review)
Review
Protein synthesis is one of the most complex and energy-consuming processes in eukaryotic cells and therefore is tightly regulated. One of the main mechanisms of translational control is post-translational modifications of the components of translational apparatus. Phosphorylation status of translation factors depends on the balanced action of kinases and phosphatases. While many kinase-dependent events are well defined, phosphatases that counteract phosphorylation are rarely determined. This mini-review focuses on the regulation of activity of translational initiation factors by serine/threonine phosphatases.
Topics: Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4E; Eukaryotic Initiation Factors; Peptide Initiation Factors; Phosphoprotein Phosphatases; Phosphoproteins; Phosphorylation; Protein Biosynthesis; Protein Kinases; Protein Phosphatase 1; Protein Phosphatase 2; Protein Processing, Post-Translational; Ribosomal Protein S6 Kinases
PubMed: 30401537
DOI: 10.1016/j.bbamcr.2018.08.006 -
Cell Death & Disease Oct 2020Protein phosphorylation and dephosphorylation govern intracellular signal transduction and cellular functions. Kinases and phosphatases are involved in the regulation... (Review)
Review
Protein phosphorylation and dephosphorylation govern intracellular signal transduction and cellular functions. Kinases and phosphatases are involved in the regulation and development of many diseases such as Alzheimer's, diabetes, and cancer. While the functions and roles of many kinases, as well as their substrates, are well understood, phosphatases are comparatively less well studied. Recent studies have shown that rather than acting on fewer and more distinct substrates like the kinases, phosphatases can recognize specific phosphorylation sites on many different proteins, making the study of phosphatases and their substrates challenging. One approach to understand the biological functions of phosphatases is through understanding their protein-protein interaction network. POPX2 (Partner of PIX 2; also known as PPM1F or CaMKP) is a serine/threonine phosphatase that belongs to the PP2C family. It has been implicated in cancer cell motility and invasiveness. This review aims to summarize the different binding partners of POPX2 phosphatase and explore the various functions of POPX2 through its interactome in the cell. In particular, we focus on the impact of POPX2 on cancer progression. Acting via its different substrates and interacting proteins, POPX2's involvement in metastasis is multifaceted and varied according to the stages of metastasis.
Topics: Cell Line, Tumor; Humans; Neoplasm Metastasis; Neoplasms; Phosphoprotein Phosphatases; Phosphorylation; Signal Transduction
PubMed: 33037179
DOI: 10.1038/s41419-020-03061-0 -
Nature Protocols Oct 2021Phosphoprotein phosphatases (PPPs) execute >90% of serine/threonine dephosphorylation in cells and tissues. While the role of PPPs in cell biology and diseases such as... (Review)
Review
Phosphoprotein phosphatases (PPPs) execute >90% of serine/threonine dephosphorylation in cells and tissues. While the role of PPPs in cell biology and diseases such as cancer, cardiac hypertrophy and Alzheimer's disease is well established, the molecular mechanisms governing and governed by PPPs still await discovery. Here we describe a chemical proteomic strategy, phosphatase inhibitor beads and mass spectrometry (PIB-MS), that enables the identification and quantification of PPPs and their posttranslational modifications in as little as 12 h. Using a specific but nonselective PPP inhibitor immobilized on beads, PIB-MS enables the efficient affinity-capture, identification and quantification of endogenous PPPs and associated proteins ('PPPome') from cells and tissues. PIB-MS captures functional, endogenous PPP subunit interactions and enables discovery of new binding partners. It performs PPP enrichment without exogenous expression of tagged proteins or specific antibodies. Because PPPs are among the most conserved proteins across evolution, PIB-MS can be employed in any cell line, tissue or organism.
Topics: Mass Spectrometry; Phosphoprotein Phosphatases; Proteomics
PubMed: 34518704
DOI: 10.1038/s41596-021-00604-3 -
The FEBS Journal Feb 2021Protein phosphorylation is a major reversible post-translational modification. Protein phosphatases function as 'critical regulators' in signaling networks through... (Review)
Review
Protein phosphorylation is a major reversible post-translational modification. Protein phosphatases function as 'critical regulators' in signaling networks through dephosphorylation of proteins, which have been phosphorylated by protein kinases. A large understanding of their working has been sourced from animal systems rather than the plant or the prokaryotic systems. The eukaryotic protein phosphatases include phosphoprotein phosphatases (PPP), metallo-dependent protein phosphatases (PPM), protein tyrosine (Tyr) phosphatases (PTP), and aspartate (Asp)-dependent phosphatases. The PPP and PPM families are serine(Ser)/threonine(Thr)-specific phosphatases (STPs), while PTP family is Tyr specific. Dual-specificity phosphatases (DsPTPs/DSPs) dephosphorylate Ser, Thr, and Tyr residues. PTPs lack sequence homology with STPs, indicating a difference in catalytic mechanisms, while the PPP and PPM families share a similar structural fold indicating a common catalytic mechanism. The catalytic cysteine (Cys) residue in the conserved HCX R active site motif of the PTPs acts as a nucleophile during hydrolysis. The PPP members require metal ions, which coordinate the phosphate group of the substrate, followed by a nucleophilic attack by a water molecule and hydrolysis. The variable holoenzyme assembly of protein phosphatase(s) and the overlap with other post-translational modifications like acetylation and ubiquitination add to their complexity. Though their functional characterization is extensively reported in plants, the mechanistic nature of their action is still being explored by researchers. In this review, we exclusively overview the plant protein phosphatases with an emphasis on their mechanistic action as well as structural characteristics.
Topics: Biocatalysis; Catalytic Domain; Models, Molecular; Phosphoprotein Phosphatases; Phosphorylation; Plant Proteins; Protein Domains; Protein Subunits; Signal Transduction; Substrate Specificity
PubMed: 32542989
DOI: 10.1111/febs.15454