title: DUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase.
abstract: 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.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Amand
authors.forename: Charlotte
authors.initials: C
authors.lastname: Erpicum
authors.forename: Khalid
authors.initials: K
authors.lastname: Bajou
authors.forename: Fabio
authors.initials: F
authors.lastname: Cerignoli
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Maud
authors.initials: M
authors.lastname: Martin
authors.forename: Franck
authors.initials: F
authors.lastname: Dequiedt
authors.forename: Pierre
authors.initials: P
authors.lastname: Drion
authors.forename: Pratibha
authors.initials: P
authors.lastname: Singh
authors.forename: Tinatin
authors.initials: T
authors.lastname: Zurashvili
authors.forename: Maud
authors.initials: M
authors.lastname: Vandereyken
authors.forename: Lucia
authors.initials: L
authors.lastname: Musumeci
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.forename: Michel
authors.initials: M
authors.lastname: Moutschen
authors.forename: Christine
authors.initials: C
authors.lastname: Gilles
authors.forename: Agnes
authors.initials: A
authors.lastname: Noel
authors.affiliation: Immunology and Infectious Diseases, GIGA-Signal Transduction, University of Liège, Liège 4000, Belgium. srahmouni@ulg.ac.be.
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D002584:Cervix Uteri / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D003094:Collagen; D004338:Drug Combinations; D054640:Dual Specificity Phosphatase 3 / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007797:Laminin; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans; D015398:Signal Transduction
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D005346:Fibroblast Growth Factors; D003094:Collagen; C512478:EGFR protein, human; D066246:ErbB Receptors; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3; C517026:Dusp3 protein, mouse