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See detailDUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase
Amand, Mathieu ULg; Erpicum, Charlotte ULg; BAJOU, Khalid ULg et al

in Molecular Cancer (2014)

Background DUSP3 phosphatase, also known as Vaccinia-H1 Related (VHR) phosphatase, encoded by DUSP3/Dusp3 gene, is a relatively small member of the dual-specificity protein phosphatases. In vitro studies ... [more ▼]

Background DUSP3 phosphatase, also known as Vaccinia-H1 Related (VHR) phosphatase, encoded by DUSP3/Dusp3 gene, is a relatively small member of the dual-specificity protein phosphatases. In vitro studies showed that DUSP3 is a negative regulator of ERK and JNK pathways in several cell lines. On the other hand, DUSP3 is implicated in human cancer. It has been alternatively described as having tumor suppressive and oncogenic properties. Thus, the available data suggest that DUSP3 plays complex and contradictory roles in tumorigenesis that could be cell type-dependent. Since most of these studies were performed using recombinant proteins or in cell-transfection based assays, the physiological function of DUSP3 has remained elusive. Results Using immunohistochemistry on human cervical sections, we observed a strong expression of DUSP3 in endothelial cells (EC) suggesting a contribution for this phosphatase to EC functions. DUSP3 downregulation, using RNA interference, in human EC reduced significantly in vitro tube formation on Matrigel and spheroid angiogenic sprouting. However, this defect was not associated with an altered phosphorylation of the documented in vitro DUSP3 substrates, ERK1/2, JNK1/2 and EGFR but was associated with an increased PKC phosphorylation. To investigate the physiological function of DUSP3, we generated Dusp3-deficient mice by homologous recombination. The obtained DUSP3-/- mice were healthy, fertile, with no spontaneous phenotype and no vascular defect. However, DUSP3 deficiency prevented neo-vascularization of transplanted b-FGF containing Matrigel and LLC xenograft tumors as evidenced by hemoglobin (Hb) and FITC-dextran quantifications. Furthermore, we found that DUSP3 is required for b-FGF-induced microvessel outgrowth in the aortic ring assay. Conclusions All together, our data identify DUSP3 as a new important player in angiogenesis. [less ▲]

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See detailPP2A regulatory subunit Balpha controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.
Martin, Maud ULg; Geudens, Ilse; Bruyr, Jonathan et al

in EMBO Journal (2013)

To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens ... [more ▼]

To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Balpha regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Balpha in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Balpha in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Balpha controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Balpha, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Balpha/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion. [less ▲]

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See detailHost-pathogen interactome mapping for HTLV-1 and -2 retroviruses.
Simonis, Nicolas; Rual, Jean-Francois; Lemmens, Irma et al

in Retrovirology (2012), 9

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 both target T lymphocytes, yet induce radically different phenotypic outcomes. HTLV-1 is a causative agent of Adult T-cell leukemia (ATL ... [more ▼]

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 both target T lymphocytes, yet induce radically different phenotypic outcomes. HTLV-1 is a causative agent of Adult T-cell leukemia (ATL), whereas HTLV-2, highly similar to HTLV-1, causes no known overt disease. HTLV gene products are engaged in a dynamic struggle of activating and antagonistic interactions with host cells. Investigations focused on one or a few genes have identified several human factors interacting with HTLV viral proteins. Most of the available interaction data concern the highly investigated HTLV-1 Tax protein. Identifying shared and distinct host-pathogen protein interaction profiles for these two viruses would enlighten how they exploit distinctive or common strategies to subvert cellular pathways toward disease progression. RESULTS: We employ a scalable methodology for the systematic mapping and comparison of pathogen-host protein interactions that includes stringent yeast two-hybrid screening and systematic retest, as well as two independent validations through an additional protein interaction detection method and a functional transactivation assay. The final data set contained 166 interactions between 10 viral proteins and 122 human proteins. Among the 166 interactions identified, 87 and 79 involved HTLV-1 and HTLV-2 -encoded proteins, respectively. Targets for HTLV-1 and HTLV-2 proteins implicate a diverse set of cellular processes including the ubiquitin-proteasome system, the apoptosis, different cancer pathways and the Notch signaling pathway. CONCLUSIONS: This study constitutes a first pass, with homogeneous data, at comparative analysis of host targets for HTLV-1 and -2 retroviruses, complements currently existing data for formulation of systems biology models of retroviral induced diseases and presents new insights on biological pathways involved in retroviral infection. [less ▲]

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See detailA new role for the PP2A regulatory subunit Balpha in angiogenesis
Martin, Maud ULg

Conference (2010)

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See detailRecent insights into Protein Phosphatase 2A structure and regulation : The reason why PP2A is no longer considered as a lazy passive housekeeping enzyme
Martin, Maud ULg; Kettmann, Richard ULg; Dequiedt, Franck ULg

in Biotechnologie, Agronomie, Société et Environnement = Biotechnology, Agronomy, Society and Environment [=BASE] (2010), 14(1), 243-252

Reversible protein phosphorylation is a major intracellular mechanism for controlling many important physiological activities. In the past, most of the attention was focused primarily on protein kinases ... [more ▼]

Reversible protein phosphorylation is a major intracellular mechanism for controlling many important physiological activities. In the past, most of the attention was focused primarily on protein kinases and on their regulation, mainly because phosphatases were then viewed as simple housekeeping enzymes. But advances in the understanding of phosphatases make now clear that protein phosphatases are dynamic and highly regulated enzymes and are as important as kinases in the regulation of cellular processes involving protein phosphorylation. Protein phosphatase 2A (PP2A) is a very abundant -it accounts for as much as 1% of total cellular protein-, ubiquitous and remarkably conserved enzyme. By dephosphorylating a plethora of cellular proteins, it is involved in the regulation of nearly all cellular activities. [less ▲]

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See detailClass IIa histone deacetylases: conducting development and differentiation.
Martin, Maud ULg; Kettmann, Richard ULg; Dequiedt, Franck ULg

in International Journal of Developmental Biology (2009), 53(2-3), 291-301

The emergence of specialized cell types and their organisation into organs and tissues involve the temporal modulation of many genes that are essential for coordinating the correct timing of instructive ... [more ▼]

The emergence of specialized cell types and their organisation into organs and tissues involve the temporal modulation of many genes that are essential for coordinating the correct timing of instructive signals. These transcriptional changes are orchestrated with a precision that reminds that of a classical symphony. Extracellular signals are transmitted to key integrators, which then orchestrate activation or repression of specific genes. In the last decade, class IIa HDACs have emerged as crucial regulators in various developmental and differentiation processes. This review focuses on the latest studies that have provided new insights into the biological functions of class IIa HDACs and discusses important aspects of their regulation. Elucidating cellular and molecular mechanisms by which functions of class IIa HDACs are modulated could potentially lead to new therapeutic opportunities for various diseases. [less ▲]

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See detailCrucial role of reversible phosphorylation in the mechanisms governing the biological functions of class IIa Histone Deacetylases
Martin, Maud ULg

Doctoral thesis (2009)

Regulation of class IIa histone deacetylases (HDACs) phosphorylation is crucial because it provides the opportunity to control important developmental processes associated with these key enzymes. Indeed ... [more ▼]

Regulation of class IIa histone deacetylases (HDACs) phosphorylation is crucial because it provides the opportunity to control important developmental processes associated with these key enzymes. Indeed, the transcriptional repressor activity of class IIa HDAC is controlled via their phosphorylation-dependent nucleo-cytoplasmic shuttling. While a lot of efforts have been directed towards the identification of the inactivating kinases that phosphorylate class IIa HDACs, the identity of the antagonist phosphatase remained an open question. During this work, we found that protein phosphatase 2A (PP2A) is responsible for dephosphorylating the class IIa HDACs member HDAC7, thereby regulating its subcellular localization and repressor activity. In order to validate our model, functional consequences of these findings was illustrated during the two main biological processes involving HDAC7, i.e. T-cells apoptosis during negative selection and endothelial cells angiogenic activities during vascular network formation. Cellular PP2A represents a large population of trimeric holoenzymes containing a variable regulatory subunit, whose identity has a crucial role in determining the specificity of PP2A catalytic activity. In an effort to characterize the regulation of HDAC7 dephopshorylation, we identified the relevant PP2A holoenzyme regulating HDAC7 function during vasculogenesis and we found that, among diverse regulatory subunit isoforms, PP2A-Bα uniquely regulates endothelial cell angiogenic properties. PP2A-Bα silencing using small interfering RNAs results in a significant inhibition of endothelial cell tube formation and migration. These results establish PP2A, and more precisely the Bα containg PP2A holoenzyme, as an essential element in the regulation of the class IIa HDACs HDAC7 and unravel a first developmental function for the PP2A regulatory subunit Bα in the genesis of blood vessels. [less ▲]

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See detailProtein Phosphatase 2a Controls The Activity Of Histone Deacetylase 7 During T Cell Apoptosis And Angiogenesis
Martin, Maud ULg; Potente, M.; Janssens, V. et al

in Proceedings of the National Academy of Sciences of the United States of America (2008), 105(12), 4727-4732

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See detailClass IIa histone deacetylases: regulating the regulators.
Martin, Maud ULg; Kettmann, Richard ULg; Dequiedt, Franck ULg

in Oncogene (2007), 26(37),

n the last decade, the identification of enzymes that regulate acetylation of histones and nonhistone proteins has revealed the key role of dynamic acetylation and deacetylation in various cellular ... [more ▼]

n the last decade, the identification of enzymes that regulate acetylation of histones and nonhistone proteins has revealed the key role of dynamic acetylation and deacetylation in various cellular processes. Mammalian histone deacetylases (HDACs), which catalyse the removal of acetyl groups from lysine residues, are grouped into three classes, on the basis of similarity to yeast counterparts. An abundance of experimental evidence has established class IIa HDACs as crucial transcriptional regulators of various developmental and differentiation processes. In the past 5 years, a tremendous effort has been dedicated to characterizing the regulation of these enzymes. In this review, we summarize the latest discoveries in the field and discuss the molecular and structural determinants of class IIa HDACs regulation. Finally, we emphasize that comprehension of the mechanisms underlying class IIa HDAC functions is essential for potential therapeutic applications. [less ▲]

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See detailNew Role For Hpar-1 Kinases Emk And C-Tak1 In Regulating Localization And Activity Of Class Iia Histone Deacetylases
Dequiedt, Franck ULg; Martin, Maud ULg; Von Blume, Julia et al

in Molecular and Cellular Biology (2006), 26(19), 7086-102

Class IIa histone deacetylases (HDACs) are found both in the cytoplasm and in the nucleus where they repress genes involved in several major developmental programs. In response to specific signals, the ... [more ▼]

Class IIa histone deacetylases (HDACs) are found both in the cytoplasm and in the nucleus where they repress genes involved in several major developmental programs. In response to specific signals, the repressive activity of class IIa HDACs is neutralized through their phosphorylation on multiple N-terminal serine residues and 14-3-3-mediated nuclear exclusion. Here, we demonstrate that class IIa HDACs are subjected to signal-independent nuclear export that relies on their constitutive phosphorylation. We identify EMK and C-TAK1, two members of the microtubule affinity-regulating kinase (MARK)/Par-1 family, as regulators of this process. We further show that EMK and C-TAK1 phosphorylate class IIa HDACs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function. Using HDAC7 as a paradigm, we extend these findings by demonstrating that signal-independent phosphorylation of the most N-terminal serine residue by the MARK/Par-1 kinases, i.e., Ser155, is a prerequisite for the phosphorylation of the nearby 14-3-3 site, Ser181. We propose that this multisite hierarchical phosphorylation by a variety of kinases allows for sophisticated regulation of class IIa HDACs function. [less ▲]

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