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Multiple Functions of the Eya Phosphotyrosine Phosphatase.

ABSTRACT: Eyes absent (Eya), a protein conserved from plants to humans and best characterized as a transcriptional coactivator, is also the prototype for a novel class of eukaryotic aspartyl protein tyrosine phosphatases. This minireview discusses recent breakthroughs in elucidating the substrates and cellular events regulated by Eya's tyrosine phosphatase function and highlights some of the complexities, new questions, and surprises that have emerged from efforts to understand how Eya's unusual multifunctionality influences developmental regulation and signaling.

SUBMITTER: Rebay I

PROVIDER: S-EPMC4760226 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Multiple Functions of the Eya Phosphotyrosine Phosphatase.

Rebay Ilaria I

Molecular and cellular biology 20151214 5

Eyes absent (Eya), a protein conserved from plants to humans and best characterized as a transcriptional coactivator, is also the prototype for a novel class of eukaryotic aspartyl protein tyrosine phosphatases. This minireview discusses recent breakthroughs in elucidating the substrates and cellular events regulated by Eya's tyrosine phosphatase function and highlights some of the complexities, new questions, and surprises that have emerged from efforts to understand how Eya's unusual multifunc ...[more]

PMID: 26667035

Similar Datasets

The EYA tyrosine phosphatase activity is pro-angiogenic and is inhibited by benzbromarone.

Project description:Eyes Absents (EYA) are multifunctional proteins best known for their role in organogenesis. There is accumulating evidence that overexpression of EYAs in breast and ovarian cancers, and in malignant peripheral nerve sheath tumors, correlates with tumor growth and increased metastasis. The EYA protein is both a transcriptional activator and a tyrosine phosphatase, and the tyrosine phosphatase activity promotes single cell motility of mammary epithelial cells. Since EYAs are expressed in vascular endothelial cells and cell motility is a critical feature of angiogenesis we investigated the role of EYAs in this process. Using RNA interference techniques we show that EYA3 depletion in human umbilical vein endothelial cells inhibits transwell migration as well as Matrigel-induced tube formation. To specifically query the role of the EYA tyrosine phosphatase activity we employed a chemical biology approach. Through an experimental screen the uricosuric agents Benzbromarone and Benzarone were found to be potent EYA inhibitors, and Benzarone in particular exhibited selectivity towards EYA versus a representative classical protein tyrosine phosphatase, PTP1B. These compounds inhibit the motility of mammary epithelial cells over-expressing EYA2 as well as the motility of endothelial cells. Furthermore, they attenuate tubulogenesis in matrigel and sprouting angiogenesis in the ex vivo aortic ring assay in a dose-dependent fashion. The anti-angiogenic effect of the inhibitors was also demonstrated in vivo, as treatment of zebrafish embryos led to significant and dose-dependent defects in the developing vasculature. Taken together our results demonstrate that the EYA tyrosine phosphatase activity is pro-angiogenic and that Benzbromarone and Benzarone are attractive candidates for repurposing as drugs for the treatment of cancer metastasis, tumor angiogenesis, and vasculopathies.

| S-EPMC3335822 | biostudies-literature

Activation of multiple pH-regulatory pathways in granulocytes by a phosphotyrosine phosphatase antagonist.

Project description:Activated phagocytes undergo a massive burst of metabolic acid generation, yet must be able to maintain their cytosolic pH (pHi) within physiological limits. Peroxides of vanadate (V(4+)-OOH), potent inhibitors of phosphotyrosine phosphatases, have recently been shown to produce activation of the respiratory burst in HL60 granulocytes. We therefore investigated the effects of V(4+)-OOH on pHi homoeostasis in HL60 granulocytes, using a pH-sensitive fluorescent dye. V(4+)-OOH stimulation induced a biphasic pH change: a transient cytosolic acidification followed by a significant alkalinization. The initial acidification was prevented by inhibition of the NADPH oxidase and was absent in undifferentiated cells lacking oxidase activity. Analysis of the alkalinization phase demonstrated the involvement of the Na+/H+ antiporter, and also provided evidence for activation of two alternative H(+)-extrusion pathways: a bafilomycin-sensitive component, likely reflecting vacuolar-type H(+)-ATPase activity, and a Zn(2+)-sensitive H(+)-conductive pathway. Our results indicate that V(4+)-OOH stimulation not only activated the NADPH oxidase but concomitantly stimulated H(+)-extrusion pathways, enabling the cells to compensate for the massive production of intracellular H+ associated with the respiratory burst.

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Phosphotyrosine phosphatase R3 receptors: Origin, evolution and structural diversification.

Project description:Subtype R3 phosphotyrosine phosphatase receptors (R3 RPTPs) are single-spanning membrane proteins characterized by a unique modular composition of extracellular fibronectin repeats and a single cytoplasmatic protein tyrosine phosphatase (PTP) domain. Vertebrate R3 RPTPs consist of five members: PTPRB, PTPRJ, PTPRH and PTPRO, which dephosphorylate tyrosine residues, and PTPRQ, which dephosphorylates phophoinositides. R3 RPTPs are considered novel therapeutic targets in several pathologies such as ear diseases, nephrotic syndromes and cancer. R3 RPTP vertebrate receptors, as well as their known invertebrate counterparts from animal models: PTP52F, PTP10D and PTP4e from the fruitfly Drosophila melanogaster and F44G4.8/DEP-1 from the nematode Caenorhabditis elegans, participate in the regulation of cellular activities including cell growth and differentiation. Despite sharing structural and functional properties, the evolutionary relationships between vertebrate and invertebrate R3 RPTPs are not fully understood. Here we gathered R3 RPTPs from organisms covering a broad evolutionary distance, annotated their structure and analyzed their phylogenetic relationships. We show that R3 RPTPs (i) have probably originated in the common ancestor of animals (metazoans), (ii) are variants of a single ancestral gene in protostomes (arthropods, annelids and nematodes); (iii) a likely duplication of this ancestral gene in invertebrate deuterostomes (echinodermes, hemichordates and tunicates) generated the precursors of PTPRQ and PTPRB genes, and (iv) R3 RPTP groups are monophyletic in vertebrates and have specific conserved structural characteristics. These findings could have implications for the interpretation of past studies and provide a framework for future studies and functional analysis of this important family of proteins.

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Drosophila EYA regulates the immune response against DNA through an evolutionarily conserved threonine phosphatase motif.

Project description:Innate immune responses against DNA are essential to counter both pathogen infections and tissue damages. Mammalian EYAs were recently shown to play a role in regulating the innate immune responses against DNA. Here, we demonstrate that the unique Drosophila eya gene is also involved in the response specific to DNA. Haploinsufficiency of eya in mutants deficient for lysosomal DNase activity (DNaseII) reduces antimicrobial peptide gene expression, a hallmark for immune responses in flies. Like the mammalian orthologues, Drosophila EYA features a N-terminal threonine and C-terminal tyrosine phosphatase domain. Through the generation of a series of mutant EYA fly strains, we show that the threonine phosphatase domain, but not the tyrosine phosphatase domain, is responsible for the innate immune response against DNA. A similar role for the threonine phosphatase domain in mammalian EYA4 had been surmised on the basis of in vitro studies. Furthermore EYA associates with IKK? and full-length RELISH, and the induction of the IMD pathway-dependent antimicrobial peptide gene is independent of SO. Our data provide the first in vivo demonstration for the immune function of EYA and point to their conserved immune function in response to endogenous DNA, throughout evolution.

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EphA3 functions are regulated by collaborating phosphotyrosine residues.

Project description:Ephrin ligands interact with Eph receptors to regulate a wide variety of biological and pathological processes. Recent studies have identified several downstream pathways that mediate the functions of these receptors. Activation of the receptors by ephrin binding results in the phosphorylation of the receptor tyrosine residues. These phosphorylated residues serve as docking sites for many of the downstream signaling pathways. However, the relative contributions of different phosphotyrosine residues remain undefined. In the present study, we mutated each individual tyrosine residues in the cytoplasmic domain of EphA3 receptor and studied the effects using cell migration, process retraction, and growth cone collapse assays. Stimulation of the EphA3 receptor with ephrin-A5 inhibits 293A cell migration, reduces NG108-15 cell neurite outgrowth, and induces growth cone collapse in hippocampal neurons. Mutation of either Y602 or Y779 alone partially decreases EphA3-induced responses. Full abrogation can only be achieved with mutations of both Y602 and Y779. These observations suggest a collaborative model of different downstream pathways.

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[Phosphotyrosine]protein phosphatase in rat brain. A major [phosphotyrosine]protein phosphatase is a 23 kDa protein distinct from acid phosphatase.

Project description:A [phosphotyrosine]protein phosphatase (PTPPase) was purified almost to homogeneity from rat brain, with [32P]p130gag-fps, an oncogene product of Fujinami sarcoma virus, as substrate. The characteristics of the purified preparation of PTPPase were as follows: the enzyme was a monomer with a molecular mass of 23 kDa; its optimum pH was 5.0-5.5; its activity was not dependent on bivalent cations; its activity was strongly inhibited by sodium vanadate, but was not inhibited by ZnCl2, L(+)-tartrate or NaF; it catalysed the dephosphorylation of [32P]p130gag-fps, [[32P]Tyr]casein, p-nitrophenyl phosphate and L-phosphotyrosine, but did not hydrolyse [[32P]Ser]tubulin, L-phosphoserine, DL-phosphothreonine, 5'-AMP, 2'-AMP or beta-glycerophosphate significantly. During the purification, most of the PTPPase activity was recovered in distinct fractions from those of conventional low-molecular-mass acid phosphatase (APase), which was reported to be a major PTPPase [Chernoff & Li (1985) Arch. Biochem. Biophys. 240, 135-145], from DE-52 DEAE-cellulose column chromatography, and those two enzymes could be completely separated by Sephadex G-75 column chromatography. APase also showed PTPPase activity with [32P]p130gag-fps, but the specific activity was lower than that of PTPPase with molecular mass of 23 kDa, and it was not sensitive to sodium vanadate. These findings suggested that PTPPase (23 kDa) was the major and specific PTPPase in the cell.

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Transcription profiling of Drosophila tissue expressing phosphatase mutant eya shows that reducing phosphatase activity did not globally impair transcriptional output

Project description:Drosophila eye specification an development relies on a collection of transcription factors termed the retinal determination gene network (RDGN). Two members of this network, Eyes absent (EYA) and Sine oculis (SO), form a transcriptional complex in which EYA provides the transactivation function while SO provides the DNA binding activity. EYA also function as a protein tyrosine phosphatase, raising the question of whether transcriptional output is dependent or independent of phosphatase activity. To explore this, we used microarrays together with binding site analysis, quantitative real-time PCR, chromatin immunoprecipitation, genetics, and in vivo expression analysis to identify new EYA-SO targets. In parallel, we examined the expression profiles of tissue expressing phosphatase mutant eya and found that reducing phosphatase activity did not globally impair transcriptional output. Among the targets identified by our analysis was the cell cycle regulatory gene, string (stg), suggesting that EYA and SO may influence cell proliferation through transcriptional regulation of stg. Future investigation into the regulation of stg and other EYA-SO targets identified in this study will help elucidate the transcriptional circuitries whereby output from the RDGN integrates with other signaling inputs to coordinate retinal development. Experiment Overall Design: We compared gene expression across duplicate samples for controls in which eya was not overexpressed to duplicate samples in which a wildtye overexpressed eya transgene, an eya mutant transgene with the D493N mutation, which reduces phosphatase activity, and a second eya mutant transgene with the E728Q mutation, which has little is any posphatase activity.

2008-03-13 | E-GEOD-9538 | biostudies-arrayexpress

Structural analysis of human dual-specificity phosphatase 22 complexed with a phosphotyrosine-like substrate.

Project description:4-Nitrophenyl phosphate (p-nitrophenyl phosphate, pNPP) is widely used as a small molecule phosphotyrosine-like substrate in activity assays for protein tyrosine phosphatases. It is a colorless substrate that upon hydrolysis is converted to a yellow 4-nitrophenolate ion that can be monitored by absorbance at 405 nm. Therefore, the pNPP assay has been widely adopted as a quick and simple method to assess phosphatase activity and is also commonly used in assays to screen for inhibitors. Here, the first crystal structure is presented of a dual-specificity phosphatase, human dual-specificity phosphatase 22 (DUSP22), in complex with pNPP. The structure illuminates the molecular basis for substrate binding and may also facilitate the structure-assisted development of DUSP22 inhibitors.

| S-EPMC4321476 | biostudies-literature

Streptococcus pneumoniae capsule biosynthesis protein CpsB is a novel manganese-dependent phosphotyrosine-protein phosphatase.

Project description:The first four genes of the capsule locus (cps) of Streptococcus pneumoniae (cpsA to cpsD) are common to most serotypes. We have previously determined that CpsD is an autophosphorylating protein-tyrosine kinase, demonstrated that CpsC is required for CpsD tyrosine-phosphorylation, and shown that CpsB is required for dephosphorylation of CpsD. In the present study we show that CpsB is a novel manganese-dependent phosphotyrosine-protein phosphatase that belongs to the PHP (polymerase and histidinol phosphatase) family of phosphoesterases. We also show that an S. pneumoniae strain with point mutations in cpsB, affecting one of the conserved motifs of CpsB, is unencapsulated and appears to be morphologically identical to a strain in which the cpsB gene had been deleted.

| S-EPMC139577 | biostudies-literature

Increased expression of receptor phosphotyrosine phosphatase-?/? is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes.

Project description:Schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-?/? (RPTP ?/?) and that the gene encoding RPTP?/? (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTP?/? in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTP?/? (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTP?/? signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTP?/? as a therapeutic target in schizophrenia.

| S-EPMC3309478 | biostudies-literature

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