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Journal of Molecular and Cellular... Feb 2017Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby... (Review)
Review
Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Accordingly, dysfunction of this regulation can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. Here, we review AF-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in AF-pathophysiology. We highlight the mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively). Finally, we discuss the challenges for phosphatase research, potential therapeutic significance of altered phosphatase-mediated protein dephosphorylation in AF, as well as future directions.
Topics: Adenosine Diphosphate; Animals; Atrial Fibrillation; Atrial Remodeling; Calcium; Cell Communication; Enzyme Activation; Gene Expression; Humans; Molecular Targeted Therapy; Myocardial Contraction; Phosphoprotein Phosphatases
PubMed: 28077320
DOI: 10.1016/j.yjmcc.2016.12.009 -
Progress in Neurobiology Mar 2021The dual-specificity phosphatase (DUSP) family includes a heterogeneous group of protein phosphatases that dephosphorylate both phospho-tyrosine and... (Review)
Review
The dual-specificity phosphatase (DUSP) family includes a heterogeneous group of protein phosphatases that dephosphorylate both phospho-tyrosine and phospho-serine/phospho-threonine residues within a single substrate. These protein phosphatases have many substrates and modulate diverse neural functions, such as neurogenesis, differentiation, and apoptosis. DUSP genes have furthermore been associated with mental disorders such as depression and neurological disorders such as Alzheimer's disease. Herein, we review the current literature on the DUSP family of genes concerning mental and neurological disorders. This review i) outlines the structure and general functions of DUSP genes, and ii) overviews the literature on DUSP genes concerning mental and neurological disorders, including model systems, while furthermore providing perspectives for future research.
Topics: Dual-Specificity Phosphatases; Humans; Nervous System Diseases; Neurogenesis; Phosphoprotein Phosphatases
PubMed: 32905807
DOI: 10.1016/j.pneurobio.2020.101906 -
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 -
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 -
International Journal of Urology :... Jan 2017The prevalence of genitourinary cancers has been increasing rapidly worldwide over the past 10 years. Advances in diagnosis and treatment have improved the oncological... (Review)
Review
The prevalence of genitourinary cancers has been increasing rapidly worldwide over the past 10 years. Advances in diagnosis and treatment have improved the oncological outcomes of patients with genitourinary cancer. However, the precise mechanisms of cancer development are largely unknown. Among various biological mechanisms, reversible phosphorylation is crucial for regulating the activities of many proteins in cancer cells. In contrast to protein kinases, the roles of cellular protein phosphatases have not been fully elucidated. However, emerging evidence suggests that various protein phosphatases are involved in genitourinary cancer development and have potential for cancer treatment. In the present review, we focus on recent progress in protein phosphatases regarding genitourinary cancers. We also explore the development of new strategies for cancer therapy using protein phosphatase and related molecules.
Topics: Antineoplastic Agents; Carcinogenesis; Humans; Phosphoprotein Phosphatases; Phosphorylation; Prevalence; Signal Transduction; Urogenital Neoplasms
PubMed: 27577716
DOI: 10.1111/iju.13197 -
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 -
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 -
Trends in Biochemical Sciences Aug 2023Dynamic protein phosphorylation and dephosphorylation are essential regulatory mechanisms that ensure proper cellular signaling and biological functions. Deregulation of... (Review)
Review
Dynamic protein phosphorylation and dephosphorylation are essential regulatory mechanisms that ensure proper cellular signaling and biological functions. Deregulation of either reaction has been implicated in several human diseases. Here, we focus on the mechanisms that govern the specificity of the dephosphorylation reaction. Most cellular serine/threonine dephosphorylation is catalyzed by 13 highly conserved phosphoprotein phosphatase (PPP) catalytic subunits, which form hundreds of holoenzymes by binding to regulatory and scaffolding subunits. PPP holoenzymes recognize phosphorylation site consensus motifs and interact with short linear motifs (SLiMs) or structural elements distal to the phosphorylation site. We review recent advances in understanding the mechanisms of PPP site-specific dephosphorylation preference and substrate recruitment and highlight examples of their interplay in the regulation of cell division.
Topics: Humans; Phosphorylation; Phosphoprotein Phosphatases; Catalytic Domain; Holoenzymes; Substrate Specificity
PubMed: 37173206
DOI: 10.1016/j.tibs.2023.04.004 -
Protein & Cell Apr 2017The 26S proteasome at the center of the ubiquitin-proteasome system (UPS) is essential for virtually all cellular processes of eukaryotes. A common misconception about... (Review)
Review
The 26S proteasome at the center of the ubiquitin-proteasome system (UPS) is essential for virtually all cellular processes of eukaryotes. A common misconception about the proteasome is that, once made, it remains as a static and uniform complex with spontaneous and constitutive activity for protein degradation. Recent discoveries have provided compelling evidence to support the exact opposite insomuch as the 26S proteasome undergoes dynamic and reversible phosphorylation under a variety of physiopathological conditions. In this review, we summarize the history and current understanding of proteasome phosphorylation, and advocate the idea of targeting proteasome kinases/phosphatases as a new strategy for clinical interventions of several human diseases.
Topics: Animals; Humans; Phosphoprotein Phosphatases; Phosphorylation; Proteasome Endopeptidase Complex; Protein Kinases
PubMed: 28258412
DOI: 10.1007/s13238-017-0382-x -
Biochimica Et Biophysica Acta Apr 2016The phosphorylation state of the C-terminal domain of RNA polymerase II is required for the temporal and spatial recruitment of various factors that mediate... (Review)
Review
The phosphorylation state of the C-terminal domain of RNA polymerase II is required for the temporal and spatial recruitment of various factors that mediate transcription and RNA processing throughout the transcriptional cycle. Therefore, changes in CTD phosphorylation by site-specific kinases/phosphatases are critical for the accurate transmission of information during transcription. Unlike kinases, CTD phosphatases have been traditionally neglected as they are thought to act as passive negative regulators that remove all phosphate marks at the conclusion of transcription. This over-simplified view has been disputed in recent years and new data assert the active and regulatory role phosphatases play in transcription. We now know that CTD phosphatases ensure the proper transition between different stages of transcription, balance the distribution of phosphorylation for accurate termination and re-initiation, and prevent inappropriate expression of certain genes. In this review, we focus on the specific roles of CTD phosphatases in regulating transcription. In particular, we emphasize how specificity and timing of dephosphorylation are achieved for these phosphatases and consider the various regulatory factors that affect these dynamics.
Topics: Eukaryotic Cells; Phosphoprotein Phosphatases; Phosphorylation; RNA Polymerase II; Saccharomyces cerevisiae; Transcription, Genetic
PubMed: 26779935
DOI: 10.1016/j.bbapap.2016.01.007