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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 -
Experientia Jun 1981The phosphoprotein phosphatase activity of a commercial preparation of bovine intestinal alkaline phosphatase (EC 3.1.3.1) was examined using phosvitin and dentine...
The phosphoprotein phosphatase activity of a commercial preparation of bovine intestinal alkaline phosphatase (EC 3.1.3.1) was examined using phosvitin and dentine phosphoprotein as substrates. Over 90% and 70% of the phosphorus from dentine phosphoprotein and phosvitin were hydrolyzed in 2 h. The optimum pH of the enzyme for the dephosphorylation of phosvitin and dentine phosphoprotein was nearly 6. No protein phosphatase activity was observed when the alkaline phosphatases from bovine liver and pulp were investigated.
Topics: Alkaline Phosphatase; Animals; Cattle; Dental Pulp; Intestines; Kinetics; Liver; Phosphoprotein Phosphatases; Substrate Specificity
PubMed: 6266866
DOI: 10.1007/BF01990040 -
Transactions of the New York Academy of... Dec 1956
Topics: Amphibians; Animals; Cytoplasm; Embryo, Mammalian; Embryo, Nonmammalian; Phosphoprotein Phosphatases; Phosphoric Monoester Hydrolases
PubMed: 13391903
DOI: 10.1111/j.2164-0947.1956.tb00515.x -
Acta Physiologica Scandinavica Dec 1998Myosin phosphorylation is an important mechanism in regulating contractile activity of smooth muscle. The level of myosin phosphorylation depends on the balance of two... (Review)
Review
Myosin phosphorylation is an important mechanism in regulating contractile activity of smooth muscle. The level of myosin phosphorylation depends on the balance of two enzymes, myosin light chain kinase and myosin phosphatase. Recently it has been discovered that myosin phosphatase can be regulated and this renewed interest in characterization of the phosphatase. It is suggested that the myosin phosphatase is composed of three subunits: a catalytic subunit of type 1 phosphatase (delta isoform; PP1c delta); and two non-catalytic subunits, large and small (M20). The large subunit is thought to be a targeting subunit and is termed myosin phosphatase target subunit (MYPT). There are several isoforms of MYPT and two genes have been identified on human chromosomes 1 and 12. A dominant feature of MYPT is a series of ankyrin repeats at the N-terminal end of the molecule and these may be involved in binding to the catalytic subunit and to substrate, phosphorylated myosin. In addition, at the N-terminal fringe of the ankyrin motifs is a consensus PP1c binding motif. The function of the M20 subunit is not established but is known to bind to the C-terminal end of MYPT. Various interactions between subunits that might be relevant for the regulation of phosphatase activity are discussed.
Topics: Animals; Humans; Myosin-Light-Chain Phosphatase; Phosphoprotein Phosphatases; Protein Phosphatase 1
PubMed: 9887971
DOI: 10.1046/j.1365-201X.1998.00447.x -
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 -
Biochemical Society Transactions Jun 2017Protein phosphatase-6 (PP6) is a member of the PPP family of Ser/Thr phosphatases involved in intracellular signaling. PP6 is conserved among all eukaryotes, and... (Review)
Review
Protein phosphatase-6 (PP6) is a member of the PPP family of Ser/Thr phosphatases involved in intracellular signaling. PP6 is conserved among all eukaryotes, and genetics in model organisms indicates it has non-redundant functions relative to other PPP phosphatases. PP6 functions in association with conserved SAPS subunits and, in vertebrate species, forms heterotrimers with Ankrd subunits. Multiple studies have demonstrated how PP6 exerts negative control at different steps of nuclear factor kappaB signaling. Expression of PP6 catalytic subunit and the PPP6R1 subunit is especially high in hematopoietic cells and lymphoid tissues. Recent efforts at conditionally knocking out genes for PP6c or PP6R1 (SAPS1) have revealed distinctive effects on development of and signaling in lymphocytes.
Topics: Animals; Gene Expression Regulation; Genes; Humans; Lymphocytes; NF-kappa B; Phosphoprotein Phosphatases; Protein Conformation; Signal Transduction
PubMed: 28620030
DOI: 10.1042/BST20160169 -
Journal of Proteome Research Jan 2023Accurate quantification of proteomics data is essential for revealing and understanding biological signaling processes. We have recently developed a chemical proteomic...
Accurate quantification of proteomics data is essential for revealing and understanding biological signaling processes. We have recently developed a chemical proteomic strategy termed phosphatase inhibitor beads and mass spectrometry (PIB-MS) to investigate endogenous phosphoprotein phosphatase (PPP) dephosphorylation signaling. Here, we compare the robustness and reproducibility of status quo quantification methods for optimal performance and ease of implementation. We then apply PIB-MS to an array of breast cancer cell lines to determine differences in PPP signaling between subtypes. Breast cancer, a leading cause of cancer death in women, consists of three main subtypes: estrogen receptor-positive (ER+), human epidermal growth factor receptor two positive (HER2+), and triple-negative (TNBC). Although there are effective treatment strategies for ER+ and HER2+ subtypes, tumors become resistant and progress. Furthermore, TNBC has few targeted therapies. Therefore, there is a need to identify new approaches for treating breast cancers. Using PIB-MS, we distinguished TNBC from non-TNBC based on subtype-specific PPP holoenzyme composition. In addition, we identified an increase in PPP interactions with Hippo pathway proteins in TNBC. These interactions suggest that phosphatases in TNBC play an inhibitory role on the Hippo pathway and correlate with increased expression of YAP/TAZ target genes both in TNBC cell lines and in TNBC patients.
Topics: Humans; Female; Triple Negative Breast Neoplasms; Proteomics; Reproducibility of Results; Signal Transduction; Phosphoprotein Phosphatases
PubMed: 36448918
DOI: 10.1021/acs.jproteome.2c00465 -
Frontiers in Cellular and Infection... 2021Protein phosphorylation and dephosphorylation are increasingly recognized as important processes for regulating multiple physiological mechanisms. Phosphorylation is...
Protein phosphorylation and dephosphorylation are increasingly recognized as important processes for regulating multiple physiological mechanisms. Phosphorylation is carried out by protein kinases and dephosphorylation by protein phosphatases. Phosphoprotein phosphatases (PPPs), one of three families of protein serine/threonine phosphatases, have great structural diversity and are involved in regulating many cell functions. PP2C, a type of PPP, is found in , a dimorphic protozoan parasite and the causal agent of leishmaniasis. The aim of this study was to clone, purify, biochemically characterize and quantify the expression of PP2C in (PP2C). Recombinant PP2C dephosphorylated a specific threonine (with optimal activity at pH 8) in the presence of the manganese divalent cation (Mn). PP2C activity was inhibited by sanguinarine (a specific inhibitor) but was unaffected by protein tyrosine phosphatase inhibitors. Western blot analysis indicated that anti-PP2C antibodies recognized a molecule of 45.2 kDa. Transmission electron microscopy with immunodetection localized PP2C in the flagellar pocket and flagellum of promastigotes but showed poor staining in amastigotes. Interestingly, PP2C belongs to the ortholog group OG6_142542, which contains only protozoa of the family Trypanosomatidae. This suggests a specific function of the enzyme in the flagellar pocket of these microorganisms.
Topics: Humans; Leishmania; Leishmania mexicana; Leishmaniasis; Phosphoprotein Phosphatases; Phosphorylation; Serine
PubMed: 33937094
DOI: 10.3389/fcimb.2021.641356 -
Biochemical and Biophysical Research... Nov 2003The regulation of cellular processes by the modulation of protein phosphorylation/dephosphorylation is fundamental to a large number of processes in living organisms....
The regulation of cellular processes by the modulation of protein phosphorylation/dephosphorylation is fundamental to a large number of processes in living organisms. These processes are carried out by specific protein kinases and phosphatases. In this study, a previously uncharacterized gene (Rv0018c) of Mycobacterium tuberculosis, designated as mycobacterial Ser/Thr phosphatase (mstp), was cloned, expressed in Escherichia coli, and purified as a histidine-tagged protein. Purified protein (Mstp) dephosphorylated the phosphorylated Ser/Thr residues of myelin basic protein (MBP), histone, and casein but failed to dephosphorylate phospho-tyrosine residue of these substrates, suggesting that this phosphatase is specific for Ser/Thr residues. It has been suggested that mstp is a part of a gene cluster that also includes two Ser/Thr kinases pknA and pknB. We show that Mstp is a trans-membrane protein that dephosphorylates phosphorylated PknA and PknB. Southern blot analysis revealed that mstp is absent in the fast growing saprophytes Mycobacterium smegmatis and Mycobacterium fortuitum. PknA has been shown, whereas PknB has been proposed to play a role in cell division. The presence of mstp in slow growing mycobacterial species, its trans-membrane localization, and ability to dephosphorylate phosphorylated PknA and PknB implicates that Mstp may play a role in regulating cell division in M. tuberculosis.
Topics: Amino Acid Sequence; Bacterial Proteins; Enzyme Activation; Molecular Sequence Data; Mycobacterium tuberculosis; Phosphoprotein Phosphatases; Phosphorylation; Protein Serine-Threonine Kinases; Sequence Alignment; Sequence Analysis, Protein; Substrate Specificity; Tissue Distribution
PubMed: 14575702
DOI: 10.1016/j.bbrc.2003.09.173 -
Cell Motility and the Cytoskeleton 1994A protein component of isolated mitotic apparatus having a relative molecular mass of 62,000 (p62) is a substrate of a calcium/calmodulin dependent protein kinase, and...
A protein component of isolated mitotic apparatus having a relative molecular mass of 62,000 (p62) is a substrate of a calcium/calmodulin dependent protein kinase, and the phosphorylation of p62 in vitro correlates directly with microtubule disassembly. In vivo experiments have determined the phosphorylation of p62 increases after fertilization; maximum incorporation of phosphate occurs during late metaphase/early anaphase and decreases thereafter. Because the level of p62 is constant throughout the cell cycle [Johnston and Sloboda, 1992: J. Cell Biol. 119:843-54] the decrease in phosphorylation of p62 observed after anaphase onset is most likely due to the action of a phosphatase. By examination of the relative amount of phosphorylated p62 which remained radiolabeled as a function of time using a standard in vitro phosphorylation assay, the activity of a phosphoprotein phosphatase capable of dephosphorylating p62 in the isolated mitotic apparatus was observed. To characterize the p62 phosphatase, okadaic acid and calyculin A were used to inhibit the dephosphorylation of p62 in vitro. It was found that specific concentrations of okadaic acid (50-500 nM) and of calyculin A (10-100 nM) were effective at inhibiting the dephosphorylation of p62 in vitro. Lower concentrations of either inhibitor had a negligible effect on dephosphorylation of p62. These data indicate the presence of phosphoprotein phosphatase type 1 activity associated with mitotic apparatus isolated from sea urchin embryos using the procedures described here. The implications of these findings relative to our understanding of the regulation of mitosis and cytokinesis are discussed.
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cell Cycle; Ethers, Cyclic; Female; Marine Toxins; Microtubule-Associated Proteins; Okadaic Acid; Oocytes; Oxazoles; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 1; Protein Processing, Post-Translational; Sea Urchins; Spindle Apparatus
PubMed: 7895292
DOI: 10.1002/cm.970290311