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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

DUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase

Authors: Mathieu Amand, Charlotte Erpicum, Khalid Bajou, Fabio Cerignoli, Silvia Blacher, Maud Martin, Franck Dequiedt, Pierre Drion, Pratibha Singh, Tinatin Zurashvili, Maud Vandereyken, Lucia Musumeci, Tomas Mustelin, Michel Moutschen, Christine Gilles, Agnes Noel, Souad Rahmouni

Published in: Molecular Cancer | Issue 1/2014

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Abstract

Background

DUSP3 phosphatase, also known as V accinia-H 1 R elated (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.
Appendix
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Literature
1.
Tautz L, Critton DA, Grotegut S: Protein tyrosine phosphatases: structure, function, and implication in human disease. Methods Mol Biol. 2013, 1053: 179-221. 10.1007/978-1-62703-562-0_13CrossRefPubMed
2.
Patterson KI, Brummer T, O’Brien PM, Daly RJ: Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J. 2009, 418: 475-489.CrossRefPubMed
3.
Dhillon AS, Hagan S, Rath O, Kolch W: MAP kinase signalling pathways in cancer. Oncogene. 2007, 26: 3279-3290. 10.1038/sj.onc.1210421CrossRefPubMed
4.
Lawrence MC, Jivan A, Shao C, Duan L, Goad D, Zaganjor E, Osborne J, McGlynn K, Stippec S, Earnest S, Chen W, Cobb MH: The roles of MAPKs in disease. Cell Res. 2008, 18: 436-442. 10.1038/cr.2008.37CrossRefPubMed
5.
Kim EK, Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010, 1802: 396-405. 10.1016/j.bbadis.2009.12.009CrossRefPubMed
6.
Nunes-Xavier C, Roma-Mateo C, Rios P, Tarrega C, Cejudo-Marin R, Tabernero L, Pulido R: Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anticancer Agents Med Chem. 2011, 11: 109-132. 10.2174/187152011794941190CrossRefPubMed
7.
Ishibashi T, Bottaro DP, Chan A, Miki T, Aaronson SA: Expression cloning of a human dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1992, 89: 12170-12174. 10.1073/pnas.89.24.12170PubMedCentralCrossRefPubMed
8.
Yuvaniyama J, Denu JM, Dixon JE, Saper MA: Crystal structure of the dual specificity protein phosphatase VHR. Science. 1996, 272: 1328-1331. 10.1126/science.272.5266.1328CrossRefPubMed
9.
Alonso A, Saxena M, Williams S, Mustelin T: Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J Biol Chem. 2001, 276: 4766-4771. 10.1074/jbc.M006497200CrossRefPubMed
10.
Wang JY, Yeh CL, Chou HC, Yang CH, Fu YN, Chen YT, Cheng HW, Huang CY, Liu HP, Huang SF, Chen YR: Vaccinia H1-related phosphatase is a phosphatase of ErbB receptors and is down-regulated in non-small cell lung cancer. J Biol Chem. 2011, 286: 10177-10184. 10.1074/jbc.M110.163295PubMedCentralCrossRefPubMed
11.
Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens R, Zhu C, Louis-dit-Sully C, Moutschen M, Jiang W, Mustelin T: Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat Cell Biol. 2006, 8: 524-531. 10.1038/ncb1398CrossRefPubMed
12.
Cerignoli F, Rahmouni S, Ronai Z, Mustelin T: Regulation of MAP kinases by the VHR dual-specific phosphatase: implications for cell growth and differentiation. Cell Cycle. 2006, 5: 2210-2215. 10.4161/cc.5.19.3267CrossRefPubMed
13.
Henkens R, Delvenne P, Arafa M, Moutschen M, Zeddou M, Tautz L, Boniver J, Mustelin T, Rahmouni S: Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR. BMC Cancer. 2008, 8: 147- 10.1186/1471-2407-8-147PubMedCentralCrossRefPubMed
14.
Arnoldussen YJ, Lorenzo PI, Pretorius ME, Waehre H, Risberg B, Maelandsmo GM, Danielsen HE, Saatcioglu F: The mitogen-activated protein kinase phosphatase vaccinia H1-related protein inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancer. Cancer Res. 2008, 68: 9255-9264. 10.1158/0008-5472.CAN-08-1224CrossRefPubMed
15.
Wagner KW, Alam H, Dhar SS, Giri U, Li N, Wei Y, Giri D, Cascone T, Kim JH, Ye Y, Multani AS, Chan CH, Erez B, Saigal B, Chung J, Lin HK, Wu X, Hung MC, Heymach JV, Lee MG: KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest. 2013, 123 (12): 5231-5246. 10.1172/JCI68642PubMedCentralCrossRefPubMed
16.
Hao L, ElShamy WM: BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR. Int J Cancer. 2007, 121: 39-46. 10.1002/ijc.22597CrossRefPubMed
17.
Wu S, Vossius S, Rahmouni S, Miletic AV, Vang T, Vazquez-Rodriguez J, Cerignoli F, Arimura Y, Williams S, Hayes T, Moutschen M, Vasile S, Pellecchia M, Mustelin T, Tautz L: Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells. J Med Chem. 2009, 52: 6716-6723. 10.1021/jm901016kPubMedCentralCrossRefPubMed
18.
Alonso A, Rahmouni S, Williams S, van Stipdonk M, Jaroszewski L, Godzik A, Abraham RT, Schoenberger SP, Mustelin T: Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nat Immunol. 2003, 4: 44-48. 10.1038/ni856CrossRefPubMed
19.
Turner N, Grose R: Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010, 10: 116-129. 10.1038/nrc2780CrossRefPubMed
20.
El Hour M, Moncada-Pazos A, Blacher S, Masset A, Cal S, Berndt S, Detilleux J, Host L, Obaya AJ, Maillard C, Foidart JM, Ectors F, Noel A, Lopez-Otin C: Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis. Oncogene. 2010, 29: 3025-3032. 10.1038/onc.2010.49CrossRefPubMed
21.
Berndt S, Perrier d’Hauterive S, Blacher S, Pequeux C, Lorquet S, Munaut C, Applanat M, Herve MA, Lamande N, Corvol P, van den Brule F, Frankenne F, Poutanen M, Huhtaniemi I, Geenen V, Noel A, Foidart JM: Angiogenic activity of human chorionic gonadotropin through LH receptor activation on endothelial and epithelial cells of the endometrium. Faseb J. 2006, 20: 2630-2632. 10.1096/fj.06-5885fjeCrossRefPubMed
22.
Berndt S, Blacher S, Munaut C, Detilleux J, Perrier d’Hauterive S, Huhtaniemi I, Evain-Brion D, Noel A, Fournier T, Foidart JM: Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation. Faseb J. 2013, 27: 1309-1321. 10.1096/fj.12-213686CrossRefPubMed
23.
Carmi Y, Voronov E, Dotan S, Lahat N, Rahat MA, Fogel M, Huszar M, White MR, Dinarello CA, Apte RN: The role of macrophage-derived IL-1 in induction and maintenance of angiogenesis. J Immunol. 2009, 183: 4705-4714. 10.4049/jimmunol.0901511CrossRefPubMed
24.
Blacher S, Devy L, Burbridge MF, Roland G, Tucker G, Noel A, Foidart JM: Improved quantification of angiogenesis in the rat aortic ring assay. Angiogenesis. 2001, 4: 133-142. 10.1023/A:1012251229631CrossRefPubMed
25.
Wishart MJ, Dixon JE: The archetype STYX/dead-phosphatase complexes with a spermatid mRNA-binding protein and is essential for normal sperm production. Proc Natl Acad Sci U S A. 2002, 99: 2112-2117. 10.1073/pnas.251686198PubMedCentralCrossRefPubMed
26.
Yang CY, Li JP, Chiu LL, Lan JL, Chen DY, Chuang HC, Huang CY, Tan TH: Dual-specificity phosphatase 14 (DUSP14/MKP6) negatively regulates TCR signaling by inhibiting TAB1 activation. J Immunol. 2014, 192: 1547-1557. 10.4049/jimmunol.1300989CrossRefPubMed
27.
Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H, Suzuki T, Amano K, Agarwala KL, Hasegawa Y, Bai DS, Ishihara T, Hashikawa T, Itohara S, Cornford EM, Niki H, Yamakawa K: Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet. 2002, 11: 1251-1262. 10.1093/hmg/11.11.1251CrossRefPubMed
28.
Wancket LM, Frazier WJ, Liu Y: Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease. Life Sci. 2012, 90: 237-248. 10.1016/j.lfs.2011.11.017PubMedCentralCrossRefPubMed
29.
Moncho-Amor V, Ibanez De Caceres I, Bandres E, Martinez-Poveda B, Orgaz JL, Sanchez-Perez I, Zazo S, Rovira A, Albanell J, Jimenez B, Rojo F, Belda-Iniesta C, Garcia-Foncillas J, Perona R: DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer. Oncogene. 2011, 30: 668-678. 10.1038/onc.2010.449CrossRefPubMed
30.
Tang JP, Tan CP, Li J, Siddique MM, Guo K, Chan SW, Park JE, Tay WN, Huang ZY, Li WC, Chen J, Zeng Q: VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancers. Mol Cancer. 2010, 9: 128- 10.1186/1476-4598-9-128PubMedCentralCrossRefPubMed
31.
Newton AC: Protein kinase C: structure, function, and regulation. J Biol Chem. 1995, 270: 28495-28498. 10.1074/jbc.270.48.28495CrossRefPubMed
32.
Newton AC: Protein kinase C. Seeing two domains. Curr Biol. 1995, 5: 973-976. 10.1016/S0960-9822(95)00191-6CrossRefPubMed
33.
Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ: Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science. 1998, 281: 2042-2045.CrossRefPubMed
34.
Keranen LM, Dutil EM, Newton AC: Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol. 1995, 5: 1394-1403. 10.1016/S0960-9822(95)00277-6CrossRefPubMed
35.
Edwards AS, Newton AC: Phosphorylation at conserved carboxyl-terminal hydrophobic motif regulates the catalytic and regulatory domains of protein kinase C. J Biol Chem. 1997, 272: 18382-18390. 10.1074/jbc.272.29.18382CrossRefPubMed
36.
Bornancin F, Parker PJ: Phosphorylation of protein kinase C-alpha on serine 657 controls the accumulation of active enzyme and contributes to its phosphatase-resistant state. J Biol Chem. 1997, 272: 3544-3549. 10.1074/jbc.272.6.3544CrossRefPubMed
37.
Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK: Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012, 16: 15-31. 10.1517/14728222.2011.648617PubMedCentralCrossRefPubMed
38.
Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, Gillieron C, Mackay F, Grey S, Camps M, Rommel C, Gerondakis SD, Mackay CR: Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006, 7: 274-283. 10.1038/ni1310CrossRefPubMed
39.
Zhang Y, Blattman JN, Kennedy NJ, Duong J, Nguyen T, Wang Y, Davis RJ, Greenberg PD, Flavell RA, Dong C: Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature. 2004, 430: 793-797. 10.1038/nature02764CrossRefPubMed
40.
Masson VV, Devy L, Grignet-Debrus C, Bernt S, Bajou K, Blacher S, Roland G, Chang Y, Fong T, Carmeliet P, Foidart JM, Noel A: Mouse aortic ring assay: a new approach of the molecular genetics of angiogenesis. Biol Proced Online. 2002, 4: 24-31. 10.1251/bpo30PubMedCentralCrossRef
41.
Detry B, Erpicum C, Paupert J, Blacher S, Maillard C, Bruyere F, Pendeville H, Remacle T, Lambert V, Balsat C, Ormenese S, Lamaye F, Janssens E, Moons L, Cataldo D, Kridelka F, Carmeliet P, Thiry M, Foidart JM, Struman I, Noel A: Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase. Blood. 2012, 119: 5048-5056. 10.1182/blood-2011-12-400267CrossRefPubMed
42.
Rahmouni S, Vang T, Alonso A, Williams S, van Stipdonk M, Soncini C, Moutschen M, Schoenberger SP, Mustelin T: Removal of C-terminal SRC kinase from the immune synapse by a new binding protein. Mol Cell Biol. 2005, 25: 2227-2241. 10.1128/MCB.25.6.2227-2241.2005PubMedCentralCrossRefPubMed
Metadata
Title
DUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase
Authors
Mathieu Amand
Charlotte Erpicum
Khalid Bajou
Fabio Cerignoli
Silvia Blacher
Maud Martin
Franck Dequiedt
Pierre Drion
Pratibha Singh
Tinatin Zurashvili
Maud Vandereyken
Lucia Musumeci
Tomas Mustelin
Michel Moutschen
Christine Gilles
Agnes Noel
Souad Rahmouni
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-108

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