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International Journal of Molecular... Apr 2021More than 70% of eukaryotic proteins are regulated by phosphorylation. However, the mechanism of dephosphorylation that counteracts phosphorylation is less studied.... (Review)
Review
More than 70% of eukaryotic proteins are regulated by phosphorylation. However, the mechanism of dephosphorylation that counteracts phosphorylation is less studied. Phosphatases are classified into 104 distinct groups based on substrate-specific features and the sequence homologies in their catalytic domains. Among them, dual-specificity phosphatases (DUSPs) that dephosphorylate both phosphoserine/threonine and phosphotyrosine are important for cellular homeostasis. Ssu72 is a newly studied phosphatase with dual specificity that can dephosphorylate both phosphoserine/threonine and phosphotyrosine. It is important for cell-growth signaling, metabolism, and immune activation. Ssu72 was initially identified as a phosphatase for the Ser5 and Ser7 residues of the C-terminal domain of RNA polymerase II. It prefers the configuration of the serine-proline motif within its substrate and regulates Pin1, different from other phosphatases. It has recently been reported that Ssu72 can regulate sister chromatid cohesion and the separation of duplicated chromosomes during the cell cycle. Furthermore, Ssu72 appears to be involved in the regulation of T cell receptor signaling, telomere regulation, and even hepatocyte homeostasis in response to a variety of stress and damage signals. In this review, we aim to summarize various functions of the Ssu72 phosphatase, their implications in diseases, and potential therapeutic indications.
Topics: Animals; Chromatids; Chromosomes, Human; Humans; NIMA-Interacting Peptidylprolyl Isomerase; Phosphoprotein Phosphatases; Protein Domains; RNA Polymerase II; Receptors, Antigen, T-Cell; Signal Transduction
PubMed: 33917542
DOI: 10.3390/ijms22073791 -
The Journal of Biological Chemistry Nov 2015A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance... (Review)
Review
A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity.
Topics: Animals; Humans; Nerve Tissue Proteins; Neuronal Plasticity; Phosphoprotein Phosphatases; Phosphorylation; Protein Serine-Threonine Kinases; Synaptic Transmission
PubMed: 26453308
DOI: 10.1074/jbc.R115.657262 -
Bioorganic & Medicinal Chemistry Feb 2021Cantharidin is a potent natural protein phosphatase monoterpene anhydride inhibitor secreted by several species of blister beetle, with its demethylated anhydride... (Review)
Review
Cantharidin is a potent natural protein phosphatase monoterpene anhydride inhibitor secreted by several species of blister beetle, with its demethylated anhydride analogue, (S)-palasonin, occurring as a constituent of the higher plant Butea frondosa. Cantharidin shows both potent protein phosphatase inhibitory and cancer cell cytotoxic activities, but possible preclinical development of this anhydride has been limited thus far by its toxicity. Thus, several synthetic derivatives of cantharidin have been prepared, of which some compounds exhibit improved antitumor potential and may have use as lead compounds. In the present review, the potential antitumor activity, structure-activity relationships, and development of cantharidin-based anticancer drug conjugates are summarized, with protein phosphatase-related and other types of mechanisms of action discussed. Protein phosphatases play a key role in the tumor microenvironment, and thus described herein is also the potential for developing new tumor microenvironment-targeted cancer chemotherapeutic agents, based on cantharidin and its naturally occurring analogues and synthetic derivatives.
Topics: Antineoplastic Agents, Phytogenic; Butea; Cantharidin; Cell Proliferation; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Molecular Structure; Phosphoprotein Phosphatases
PubMed: 33454654
DOI: 10.1016/j.bmc.2021.116012 -
Cell Stress & Chaperones May 2020Protein phosphatase 5 (PP5) is a serine/threonine protein phosphatase that regulates many cellular functions including steroid hormone signaling, stress response,... (Review)
Review
Protein phosphatase 5 (PP5) is a serine/threonine protein phosphatase that regulates many cellular functions including steroid hormone signaling, stress response, proliferation, apoptosis, and DNA repair. PP5 is also a co-chaperone of the heat shock protein 90 molecular chaperone machinery that assists in regulation of cellular signaling pathways essential for cell survival and growth. PP5 plays a significant role in survival and propagation of multiple cancers, which makes it a promising target for cancer therapy. Though there are several naturally occurring PP5 inhibitors, none is specific for PP5. Here, we review the roles of PP5 in cancer progression and survival and discuss the unique features of the PP5 structure that differentiate it from other phosphoprotein phosphatase (PPP) family members and make it an attractive therapeutic target.
Topics: Breast Neoplasms; Catalytic Domain; Female; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Nuclear Proteins; Phosphoprotein Phosphatases
PubMed: 32239474
DOI: 10.1007/s12192-020-01091-3 -
Scientific Reports Jul 2021Phosphoprotein phosphatase (PPP) enzymes are ubiquitous proteins involved in cellular signaling pathways and other functions. Here we have traced the origin of the PPP...
Phosphoprotein phosphatase (PPP) enzymes are ubiquitous proteins involved in cellular signaling pathways and other functions. Here we have traced the origin of the PPP sequences of Eukaryotes and their radiation. Using a bacterial PPP Hidden Markov Model (HMM) we uncovered "BacterialPPP-Like" sequences in Archaea. A HMM derived from eukaryotic PPP enzymes revealed additional, unique sequences in Archaea and Bacteria that were more like the eukaryotic PPP enzymes then the bacterial PPPs. These sequences formed the basis of phylogenetic tree inference and sequence structural analysis allowing the history of these sequence types to be elucidated. Our phylogenetic tree data strongly suggest that eukaryotic PPPs ultimately arose from ancestors in the Asgard archaea. We have clarified the radiation of PPPs within Eukaryotes, substantially expanding the range of known organisms with PPP subtypes (Bsu1, PP7, PPEF/RdgC) previously thought to have a more restricted distribution. Surprisingly, sequences from the Methanosarcinaceae (Euryarchaeota) form a strongly supported sister group to eukaryotic PPPs in our phylogenetic analysis. This strongly suggests an intimate association between an Asgard ancestor and that of the Methanosarcinaceae. This is highly reminiscent of the syntrophic association recently demonstrated between the cultured Lokiarchaeal species Prometheoarchaeum and a methanogenic bacterial species.
Topics: Amino Acid Sequence; Animals; Archaea; Bacteria; Eukaryota; Evolution, Molecular; Humans; Phosphoprotein Phosphatases; Phylogeny
PubMed: 34211082
DOI: 10.1038/s41598-021-93206-8 -
Cellular and Molecular Life Sciences :... Jul 2016Glucan phosphatases are a family of enzymes that are functionally conserved at the enzymatic level in animals and plants. These enzymes bind and dephosphorylate glycogen... (Review)
Review
Glucan phosphatases are a family of enzymes that are functionally conserved at the enzymatic level in animals and plants. These enzymes bind and dephosphorylate glycogen in animals and starch in plants. While the enzymatic function is conserved, the glucan phosphatases employ distinct mechanisms to bind and dephosphorylate glycogen or starch. The founding member of the family is a bimodular human protein called laforin that is comprised of a carbohydrate binding module 20 (CBM20) followed by a dual specificity phosphatase domain. Plants contain two glucan phosphatases: Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2). SEX4 contains a chloroplast targeting peptide, dual specificity phosphatase (DSP) domain, a CBM45, and a carboxy-terminal motif. LSF2 is comprised of simply a chloroplast targeting peptide, DSP domain, and carboxy-terminal motif. SEX4 employs an integrated DSP-CBM glucan-binding platform to engage and dephosphorylate starch. LSF2 lacks a CBM and instead utilizes two surface binding sites to bind and dephosphorylate starch. Laforin is a dimeric protein in solution and it utilizes a tetramodular architecture and cooperativity to bind and dephosphorylate glycogen. This chapter describes the biological role of glucan phosphatases in glycogen and starch metabolism and compares and contrasts their ability to bind and dephosphorylate glucans.
Topics: Binding Sites; Glucans; Multigene Family; Phosphoprotein Phosphatases; Protein Binding; Substrate Specificity
PubMed: 27147465
DOI: 10.1007/s00018-016-2249-3 -
Archives of Biochemistry and Biophysics Feb 2018Intracellular signal transduction is built on the basis of the subtle balance between phosphorylation and dephosphorylation. Ca/calmodulin-dependent protein kinase... (Review)
Review
Intracellular signal transduction is built on the basis of the subtle balance between phosphorylation and dephosphorylation. Ca/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F/POPX2) and CaMKP-N (PPM1E/POPX1) are Ser/Thr phosphatases that belong to the PPM (protein phosphatase, Mg/Mn-dependent) family. The former was discovered in rat brain as a novel protein phosphatase regulating Ca/calmodulin-dependent protein kinases (CaMKs), whereas the latter was first identified in human cDNA databases using the rat CaMKP sequence. Subsequent studies have revealed that they are involved in various cellular functions through regulation of not only CaMKs but also other protein kinases such as AMP-activated protein kinase. Furthermore, accumulating evidence shows possible involvement of CaMKP and CaMKP-N in the pathogenesis of various diseases including cancer. Therefore, the biochemistry of CaMKP and CaMKP-N largely contributes to molecular medicine targeting these phosphatases. In this review, we summarized recent progress in the enzymology and biology of CaMKP and CaMKP-N. We also focused on etiology studies in which CaMKP and CaMKP-N are involved. Based on the emerging evidence, future perspectives of studies on these phosphatases and related issues to be elucidated are discussed.
Topics: Amino Acid Sequence; Animals; Calcium; Catalytic Domain; DNA, Complementary; Disease; Humans; Phosphoprotein Phosphatases; Protein Phosphatase 2C; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Signal Transduction
PubMed: 29317228
DOI: 10.1016/j.abb.2018.01.001 -
European Journal of Medicinal Chemistry Jun 2023Phosphorylation of proteins is reversibly controlled by the kinases and phosphatases in many posttranslational regulation patterns. Protein phosphatase 5 (PPP5C) is a... (Review)
Review
Phosphorylation of proteins is reversibly controlled by the kinases and phosphatases in many posttranslational regulation patterns. Protein phosphatase 5 (PPP5C) is a serine/threonine protein phosphatase showing dual function by simultaneously exerting dephosphorylation and co-chaperone functions. Due to this special role, PPP5C was found to participate in many signal transductions related to various diseases. Abnormal expression of PPP5C results in cancers, obesity, and Alzheimer's disease, making it a potential drug target. However, the design of small molecules targeting PPP5C is struggling due to its special monomeric enzyme form and low basal activity by a self-inhibition mechanism. Through realizing the PPP5C's dual function as phosphatase and co-chaperone, more and more small molecules were found to regulate PPP5C with a different mechanism. This review aims to provide insights into PPP5C's dual function from structure to function, which could provide efficient design strategies for small molecules targeting PPP5C as therapeutic candidates.
Topics: Humans; Phosphoprotein Phosphatases; Nuclear Proteins; Neoplasms; Phosphorylation; Drug Discovery; Protein Phosphatase 2
PubMed: 37054560
DOI: 10.1016/j.ejmech.2023.115350 -
Cell Communication and Signaling : CCS Sep 2017Hedgehog signaling is evolutionarily conserved and plays a pivotal role in cell fate determination, embryonic development, and tissue renewal. As aberrant Hedgehog... (Review)
Review
Hedgehog signaling is evolutionarily conserved and plays a pivotal role in cell fate determination, embryonic development, and tissue renewal. As aberrant Hedgehog signaling is tightly associated with a broad range of human diseases, its activities must be precisely controlled. It has been known that several core components of Hedgehog pathway undergo reversible phosphorylations mediated by protein kinases and phosphatases, which acts as an effective regulatory mechanism to modulate Hedgehog signal activities. In contrast to kinases that have been extensively studied in these phosphorylation events, phosphatases were thought to function in an unspecific manner, thus obtained much less emphasis in the past. However, in recent years, increasing evidence has implicated that phosphatases play crucial and specific roles in the context of developmental signaling, including Hedgehog signaling. In this review, we present a summary of current progress on phosphatase studies in Hedgehog pathway, emphasizing the multiple employments of protein serine/threonine phosphatases during the transduction of morphogenic Hedgehog signal in both Drosophila and vertebrate systems, all of which provide insights into the importance of phosphatases in the specific regulation of Hedgehog signaling.
Topics: Animals; Hedgehog Proteins; Humans; Phosphoprotein Phosphatases; Signal Transduction
PubMed: 28931407
DOI: 10.1186/s12964-017-0191-0 -
Frontiers in Cellular and Infection... 2016are Gram negative bacterial pathogens responsible for disease in humans and economically important domesticated animals. As obligate intracellular bacteria, they must... (Review)
Review
are Gram negative bacterial pathogens responsible for disease in humans and economically important domesticated animals. As obligate intracellular bacteria, they must gain entry into a host cell where they propagate within a parasitophorous organelle that serves as an interactive interface between the bacterium and the host. Nutrient acquisition, growth, and evasion of host defense mechanisms occur from this location. In addition to these cellular and bacterial dynamics, differentiate between two morphologically distinct forms, the elementary body and reticulate body, that are optimized for either extracellular or intracellular survival, respectively. The mechanisms regulating and mediating these diverse physiological events remain largely unknown. Reversible phosphorylation, including classical two-component signaling systems, partner switching mechanisms, and the more recently appreciated bacterial Ser/Thr/Tyr kinases and phosphatases, has gained increasing attention for its role in regulating important physiological processes in bacteria including metabolism, development, and virulence. Phosphorylation modulates these events via rapid and reversible modification of protein substrates leading to changes in enzyme activity, protein oligomerization, cell signaling, and protein localization. The characterization of several conserved chlamydial protein kinases and phosphatases along with phosphoproteome analysis suggest that are capable of global and growth stage-specific protein phosphorylation. This mini review will highlight the current knowledge of protein phosphorylation in and its potential role in chlamydial physiology and, consequently, virulence. Comparisons with other minimal genome intracellular bacterial pathogens also will be addressed with the aim of illustrating the importance of this understudied regulatory mechanism on pathogenesis and the principle questions that remain unanswered.
Topics: Bacterial Proteins; Chlamydia; Gene Expression Regulation, Bacterial; Phosphoprotein Phosphatases; Phosphorylation; Protein Kinases; Protein Processing, Post-Translational; Stress, Physiological; Virulence
PubMed: 28066729
DOI: 10.3389/fcimb.2016.00197