共查询到20条相似文献,搜索用时 31 毫秒
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《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2019,1866(1):153-166
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. 相似文献
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Mitogen-activated protein MAP kinases are key signal-transducing enzymes that are activated by a wide range of extracellular stimuli. They are responsible for the induction of a number of cellular responses, such as changes in gene expression, proliferation, differentiation, cell cycle arrest and apoptosis. Although regulation of MAP kinases by a phosphorylation cascade has long been recognized as significant, their inactivation through the action of specific phosphatases has been less studied. An emerging family of structurally distinct dual-specificity serine, threonine and tyrosine phosphatases that act on MAP kinases consists of ten members in mammals, and members have been found in animals, plants and yeast. Three subgroups have been identified that differ in exon structure, sequence and substrate specificity. 相似文献
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Dual-specificity phosphatases (DSPs) constitute a subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylates phospho-Tyr, phospho-Ser and nonproteinaceous substrates. DSPs are involved in the regulation of both developmental and postnatal essential processes, such as early embryogenesis, placental development and immune responses. Several DSP genes are implicated in familial and sporadic human diseases, including tumor-related, neurological and muscle disorders, and cardiovascular and inflammatory diseases. This association ranges from disease-causative mutations to disease-risk-prone single-nucleotide polymorphisms, promoter methylation or gene duplication (most often in cancer). Deconvolution of the role of DSPs in disease is challenging. The enzymes' activities are regulated at many levels and they form part of extensive, intricate networks with other signaling components. Here, we review current knowledge of the role of cysteine-based PTP-domain DSPs in health and disease, and their suitability as putative therapeutic targets for drugs is discussed. 相似文献
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Michel Bernier 《Cell biochemistry and biophysics》2004,40(3):209-217
Insulin receptor signal transduction plays a critical role in regulating pancreatic β-cell function, notably the acute first-phase insulin release in response to glucose. The basis for insulin resistance in pancreatic β-cells is not well understood but may be related to abnormal regulation of tyrosine phosphorylation events, which, in turn, may alter organization of insulin-signaling molecules in space and time. Members of the protein tyrosine phosphatase (PTPase) family are both functionally and structurally diverse; and within the past few years data have emerged from many laboratories that suggest selectivity of the PTPase catalytic domains toward cellular substrates. Of significance, a subset of PTPases has been implicated in the regulation of insulin signaling in a number of insulin-sensitive tissues. Alteration in PTPase expression or activity has been associated with abnormal regulation of tyrosine phosphorylation events and is accompanied by modulation of insulin sensitivity in vivo. Manipulations aimed at reducing expression of physiologically relevant PTPases acting at a step proximal to the insulin receptor are accompanied by normalization of blood glucose levels and improved insulin sensitivity in both normal and diabetic animals. Hence, the development of tissue-specific gene inactivation strategies should facilitate the study of the potential role of PTPases in β-cell insulin signaling transduction. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(23):4613-4614
Comment on: Thomas Y, et al. Cell Cycle 2010; 9:4338–50. 相似文献
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Calmodulin-dependent protein phosphatase has been proposed to be an important phosphotyrosyl-protein phosphatase. The ability of the enzyme to attack autophosphorylated insulin receptor was examined and compared with the known ability of the enzyme to act on autophosphorylated epidermal-growth-factor (EGF) receptor. Purified calmodulin-dependent protein phosphatase was shown to catalyse the complete dephosphorylation of phosphotyrosyl-(insulin receptor). When compared at similar concentrations, 32P-labelled EGF receptor was dephosphorylated at greater than 3 times the rate of 32P-labelled insulin receptor; both dephosphorylations exhibited similar dependence on metal ions and calmodulin. Native phosphotyrosyl-protein phosphatases in cell extracts were also characterized. With rat liver, heart or brain, most (75%) of the native phosphatase activity against both 32P-labelled insulin and EGF receptors was recovered in the particulate fraction of the cell, with only 25% in the soluble fraction. This subcellular distribution contrasts with results of previous studies using artificial substrates, which found most of the phosphotyrosyl-protein phosphatase activity in the soluble fraction of the cell. Properties of particulate and soluble phosphatase activity against 32P-labelled insulin and EGF receptors are reported. The contribution of calmodulin-dependent protein phosphatase activity to phosphotyrosyl-protein phosphatase activity in cell fractions was determined by utilizing the unique metal-ion dependence of calmodulin-dependent protein phosphatase. Whereas Ni2+ (1 mM) markedly activated the calmodulin-dependent protein phosphatase, it was found to inhibit potently both particulate and soluble phosphotyrosyl-protein phosphatase activity. In fractions from rat liver, brain and heart, total phosphotyrosyl-protein phosphatase activity against both 32P-labelled receptors was inhibited by 99.5 +/- 6% (mean +/- S.E.M., 30 observations) by Ni2+. Results of Ni2+ inhibition studies were confirmed by other methods. It is concluded that in cell extracts phosphotyrosyl-protein phosphatases other than calmodulin-dependent protein phosphatase are the major phosphotyrosyl-(insulin receptor) and -(EGF receptor) phosphatases. 相似文献
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《Seminars in cell biology》1993,4(6):397-401
Seven protein tyrosine phosphatase (PTPase) genes have been identified in the fruit-fly Drosophila melanogaster. Four of these genes encode receptor-linked PTPases (R-PTPs) that are expressed on central nervous system axons in the embryo. Each axonal R-PTP has an extracellular domain that is homologous to vertebrate adhesion molecules and to identified mammalian R-PTPs. Two non-receptor PTPase genes have been isolated to date. One of these, corkscrew (csw), encodes an SH2 domain-containing PTPase that appears to be a homolog of mammalian PTP1D. Genetic evidence indicates that the csw PTPase is involved in the transduction of signals from receptor tyrosine kinases to their down-stream targets, which include Ras proteins. 相似文献
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The amino acid sequences of mammalian purple acid phosphatases and phosphoprotein phosphatases are shown to possess regions of significant homology. The conserved residues contain a high percentage of possible metal-binding residues. The phosphoprotein phosphatases 1, 2A and 2B are proposed to be iron-zinc metalloenzymes with active sites isostructural (or nearly so) with those of the purple phosphatases. 相似文献
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David N. Brindley Carlos Pilquil Meltem Sariahmetoglu Karen Reue 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2009,1791(9):956-961
Three lipid phosphate phosphatases (LPPs) regulate cell signaling by modifying the concentrations of a variety of lipid phosphates versus their dephosphorylated products. In particular, the LPPs are normally considered to regulate signaling by the phospholipase D (PLD) pathway by converting phosphatidate (PA) to diacylglycerol (DAG). LPP activities do modulate the accumulations of PA and DAG following PLD activation, but this could also involve an effect upstream of PLD activation. The active sites of the LPPs are on the exterior surface of plasma membranes, or on the luminal surface of internal membranes. Consequently, the actions of the LPPs in metabolizing PA formed by PLD1 or PLD2 should depend on the access of this substrate to the active site of the LPPs. Alternatively, PA generated on the cytosolic surface of membranes should be readily accessible to the family of specific phosphatidate phosphatases, namely the lipins. Presently, there is only indirect evidence for the lipins participating in cell signaling following PLD activation. So far, we know relatively little about how individual LPPs and specific phosphatidate phosphatases (lipins) modulate cell signaling through controlling the turnover of bioactive lipids that are formed after PLD activation. 相似文献
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GORDON JJ 《The Biochemical journal》1953,55(5):812-817
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Avila J 《Journal of cellular and molecular medicine》2008,12(1):258-259
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The aim of this review is to provide a synthesis of the published experimental data on protein tyrosine phosphatases from parasitic protozoa, in silico analysis based on the availability of completed genomes and to place available data for individual phosphatases from different unicellular parasites into the comparative and evolutionary context. We analysed the complement of protein tyrosine phosphatases (PTP) in several species of unicellular parasites that belong to Apicomplexa (Plasmodium; Cryptosporidium, Babesia, Theileria, and Toxoplasma), kinetoplastids (Leishmania and Trypanosoma spp.), as well as Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis and a microsporidium Encephalitozoon cuniculi. The analysis shows distinct distribution of the known families of tyrosine phosphatases in different species. Protozoan tyrosine phosphatases show considerable levels of divergence compared with their mammalian homologues, both in terms of sequence similarity between the catalytic domains and the structure of their flanking domains. This potentially makes them suitable targets for development of specific inhibitors with minimal effects on physiology of mammalian hosts. 相似文献