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Cell Oct 2009The reversible phosphorylation of proteins is accomplished by opposing activities of kinases and phosphatases. Relatively few protein serine/threonine phosphatases... (Review)
Review
The reversible phosphorylation of proteins is accomplished by opposing activities of kinases and phosphatases. Relatively few protein serine/threonine phosphatases (PSPs) control the specific dephosphorylation of thousands of phosphoprotein substrates. Many PSPs, exemplified by protein phosphatase 1 (PP1) and PP2A, achieve substrate specificity and regulation through combinatorial interactions between conserved catalytic subunits and a large number of regulatory subunits. Other PSPs, represented by PP2C and FCP/SCP, contain both catalytic and regulatory domains within the same polypeptide chain. Here, we discuss biochemical and structural investigations that advance the mechanistic understanding of the three major classes of PSPs, with a focus on PP2A.
Topics: Animals; Humans; Models, Molecular; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Phosphatase 2
PubMed: 19879837
DOI: 10.1016/j.cell.2009.10.006 -
The Biochemical Journal Dec 2018Reversible phosphorylation of proteins is a post-translational modification that regulates all aspect of life through the antagonistic action of kinases and... (Review)
Review
Reversible phosphorylation of proteins is a post-translational modification that regulates all aspect of life through the antagonistic action of kinases and phosphatases. Protein kinases are well characterized, but protein phosphatases have been relatively neglected. Protein phosphatase 1 (PP1) catalyzes the dephosphorylation of a major fraction of phospho-serines and phospho-threonines in cells and thereby controls a broad range of cellular processes. In this review, I will discuss how phosphatases were discovered, how the view that they were unselective emerged and how recent findings have revealed their exquisite selectivity. Unlike kinases, PP1 phosphatases are obligatory heteromers composed of a catalytic subunit bound to one (or two) non-catalytic subunit(s). Based on an in-depth study of two holophosphatases, I propose the following: selective dephosphorylation depends on the assembly of two components, the catalytic subunit and the non-catalytic subunit, which serves as a high-affinity substrate receptor. Because functional complementation of the two modules is required to produce a selective holophosphatase, one can consider that they are split enzymes. The non-catalytic subunit was often referred to as a regulatory subunit, but it is, in fact, an essential component of the holoenzyme. In this model, a phosphatase and its array of mostly orphan substrate receptors constitute the split protein phosphatase system. The set of potentially generalizable principles outlined in this review may facilitate the study of these poorly understood enzymes and the identification of their physiological substrates.
Topics: Animals; Enzyme Inhibitors; Humans; Phosphoprotein Phosphatases; Phosphorylation; Protein Multimerization; Protein Phosphatase 1; Protein Phosphatase 2; Protein Subunits; Substrate Specificity
PubMed: 30523060
DOI: 10.1042/BCJ20170726 -
Biochimica Et Biophysica Acta.... Jan 2019This review presents the accumulating evidence for the roles of protein phosphatase 6 (PP6) in cell cycle, DNA damage repair, inflammatory signaling, lymphocyte... (Review)
Review
This review presents the accumulating evidence for the roles of protein phosphatase 6 (PP6) in cell cycle, DNA damage repair, inflammatory signaling, lymphocyte development, virus infection, tumor formation/progression, cell/tissue size, and non-coding RNA-mediated regulation. PP6 is an evolutionarily conserved and ubiquitously expressed Ser/Thr protein phosphatase most closely related to protein phosphatase 2A (PP2A) and protein phosphatase 4 (PP4). Although abundantly expressed in cells with multiple roles in cellular signaling, PP6 has received less attention than its close relative PP2A. Many studies used okadaic acid as "PP2A" inhibitor, even though these toxins also inhibit PP6 activity, so effects of the inhibitor could have been due to inhibition of both phosphatases. PP6 has its own dedicated subunits that assemble into heterotrimers that presumably fulfill its discrete functions in cells.
Topics: Cell Cycle; Cell Size; DNA Repair; Gene Expression Regulation; Inflammation; Lymphocytes; Neoplasms; Phosphoprotein Phosphatases; RNA, Untranslated; Signal Transduction; Virus Diseases
PubMed: 30036567
DOI: 10.1016/j.bbamcr.2018.07.015 -
Biochimica Et Biophysica Acta.... Jan 2019Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as... (Review)
Review
Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as serine/threonine, tyrosine-, and histidine-phosphorylated proteins. To accomplish these tasks, HAD phosphatases are equipped with cap domains that control access to the active site and provide substrate specificity determinants. A number of capped HAD phosphatases impact protein phosphorylation, although structural data are consistent with small metabolite substrates rather than protein substrates. This review discusses the structures, functions and disease implications of the three closely related, capped HAD phosphatases pyridoxal phosphatase (PDXP or chronophin), phosphoglycolate phosphatase (PGP, also termed AUM or glycerol phosphatase) and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP or HDHD2B). Evidence in support of small metabolite and protein phosphatase activity is discussed in the context of the diversity of their biological functions.
Topics: Actin Cytoskeleton; Animals; Humans; Hydrolases; Inorganic Pyrophosphatase; Neoplasms; Phosphoprotein Phosphatases; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Tyrosine Phosphatases
PubMed: 30030002
DOI: 10.1016/j.bbamcr.2018.07.007 -
MBio Oct 2023Pyrin, a unique cytosolic receptor, initiates inflammatory responses against RhoA-inactivating bacterial toxins and effectors like YopE and YopT. Understanding pyrin...
Pyrin, a unique cytosolic receptor, initiates inflammatory responses against RhoA-inactivating bacterial toxins and effectors like YopE and YopT. Understanding pyrin regulation is crucial due to its association with dysregulated inflammatory responses, including Familial Mediterranean Fever (FMF), linked to pyrin gene mutations. FMF mutations historically acted as a defense mechanism against plague. Negative regulation of pyrin through PKN phosphorylation is well established, with using the YopM effector to promote pyrin phosphorylation and counteract its activity. This study highlights the importance of phosphoprotein phosphatase activity in positively regulating pyrin inflammasome assembly in phagocytic cells of humans and mice. Oligomeric murine pyrin has S205 phosphorylated before inflammasome assembly, and this study implicates the dephosphorylation of murine pyrin S205 by two catalytic subunits of PP2A in macrophages. These findings offer insights for investigating the regulation of oligomeric pyrin and the balance of kinase and phosphatase activity in pyrin-associated infectious and autoinflammatory diseases.
Topics: Humans; Animals; Mice; Inflammasomes; Pyrin; Protein Processing, Post-Translational; Macrophages; Phosphoprotein Phosphatases; Mutation
PubMed: 37787552
DOI: 10.1128/mbio.02066-23 -
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 -
Biochimica Et Biophysica Acta.... Jan 2019The serine/threonine phosphatase PP2A regulates a vast portion of the phosphoproteome including pathways involved in apoptosis, proliferation and DNA damage response and... (Review)
Review
The serine/threonine phosphatase PP2A regulates a vast portion of the phosphoproteome including pathways involved in apoptosis, proliferation and DNA damage response and PP2A inactivation is a vital step in malignant transformation. Many groups have explored the therapeutic venue of combining PP2A reactivation with kinase inhibition to counteract the very changes in tumor suppressors and oncogenes that lead to cancer development. Conversely, inhibition of PP2A to complement chemotherapy and radiation-induced cancer cell death is also an area of active investigation. Here we review the studies that utilize PP2A targeted agents as combination therapy in cancer. A potential role for PP2A in tumor immunity is also highlighted.
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Phosphoprotein Phosphatases; Protein Phosphatase 2; Protein Subunits; Signal Transduction
PubMed: 30401535
DOI: 10.1016/j.bbamcr.2018.08.020 -
Current Genetics Feb 2019The phosphorylation status of a protein is highly regulated and is determined by the opposing activities of protein kinases and protein phosphatases within the cell.... (Review)
Review
The phosphorylation status of a protein is highly regulated and is determined by the opposing activities of protein kinases and protein phosphatases within the cell. While much is known about the protein kinases found in Saccharomyces cerevisiae, the protein phosphatases are much less characterized. Of the 127 protein kinases in yeast, over 90% are in the same evolutionary lineage. In contrast, protein phosphatases are fewer in number (only 43 have been identified in yeast) and comprise multiple, distinct evolutionary lineages. Here we review the protein phosphatase families of yeast with regard to structure, catalytic mechanism, regulation, and signal transduction participation.
Topics: Amino Acid Sequence; Gene Expression Regulation, Fungal; Models, Molecular; Phosphoprotein Phosphatases; Phosphorylation; Protein Conformation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sequence Homology; Signal Transduction
PubMed: 30225534
DOI: 10.1007/s00294-018-0884-y -
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 -
BMC Plant Biology Jun 2016SNF1-related protein kinases 2 (SnRK2s) are key regulators of the plant response to osmotic stress. They are transiently activated in response to drought and salinity....
BACKGROUND
SNF1-related protein kinases 2 (SnRK2s) are key regulators of the plant response to osmotic stress. They are transiently activated in response to drought and salinity. Based on a phylogenetic analysis SnRK2s are divided into three groups. The classification correlates with their response to abscisic acid (ABA); group 1 consists SnRK2s non-activated in response to ABA, group 2, kinases non-activated or weakly activated (depending on the plant species) by ABA treatment, and group 3, ABA-activated kinases. The activity of all SnRK2s is regulated by phosphorylation. It is well established that clade A phosphoprotein phosphatases 2C (PP2Cs) are negative regulators of ABA-activated SnRK2s, whereas regulators of SnRK2s from group 1 remain unidentified.
RESULTS
Here, we show that ABI1, a PP2C clade A phosphatase, interacts with SnRK2.4, member of group 1 of the SnRK2 family, dephosphorylates Ser158, whose phosphorylation is needed for the kinase activity, and inhibits the kinase, both in vitro and in vivo. Our data indicate that ABI1 and the kinase regulate primary root growth in response to salinity; the phenotype of ABI1 knockout mutant (abi1td) exposed to salt stress is opposite to that of the snrk2.4 mutant. Moreover, we show that the activity of SnRK2s from group 1 is additionally regulated by okadaic acid-sensitive phosphatase(s) from the phosphoprotein phosphatase (PPP) family.
CONCLUSIONS
Phosphatase ABI1 and okadaic acid-sensitive phosphatases of the PPP family are negative regulators of salt stress-activated SnRK2.4. The results show that ABI1 inhibits not only the ABA-activated SnRK2s but also at least one ABA-non-activated SnRK2, suggesting that the phosphatase is involved in the cross talk between ABA-dependent and ABA-independent stress signaling pathways in plants.
Topics: Abscisic Acid; Arabidopsis; Arabidopsis Proteins; Okadaic Acid; Phosphoprotein Phosphatases; Phosphorylation; Phylogeny; Protein Binding; Protein Serine-Threonine Kinases; Sodium Chloride
PubMed: 27297076
DOI: 10.1186/s12870-016-0817-1