{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T18:38:43Z","timestamp":1761676723850,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,7]],"date-time":"2019-04-07T00:00:00Z","timestamp":1554595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation for Science and Technology (FCT), Portugal","award":["IF\/00614\/2014","IF\/00614\/2014\/CP12340006","UID\/BIM\/04773\/2013CBMR1334","WELCOMEII\/57\/UALG\/1050\/2011"],"award-info":[{"award-number":["IF\/00614\/2014","IF\/00614\/2014\/CP12340006","UID\/BIM\/04773\/2013CBMR1334","WELCOMEII\/57\/UALG\/1050\/2011"]}]},{"name":"ERASMUS Mundus fellowship (EMQAL)","award":["FPAnr2013-0225"],"award-info":[{"award-number":["FPAnr2013-0225"]}]},{"name":"Ollie Young Foundation","award":["1148511"],"award-info":[{"award-number":["1148511"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hydrogen peroxide (H2O2) is a main second messenger in oncogenic signaling networks including the Ras and the growth factor receptor pathways. This is achieved predominantly through the oxidation of redox-sensitive cysteine (Cys) residues in proteins resulting in changes to their structure and function. We previously identified annexin A2 (ANXA2) as a redox regulatory protein that plays an important cellular role during oxidative stress and also promoting tumorigenesis. Here we investigated the role of ANXA2 in the regulation of H2O2-dependent signaling that drives tumor progression. We show that depletion of ANXA2 leads to the enhanced activation of AKT following either EGF\/EGFR stimulation or oncogenic Ras transformation. The phosphatase and tensin homologue (PTEN) protein negatively regulates the PI3K\/AKT pathway. We demonstrate that ANXA2 via its reactive Cys-8 residue, binds to PTEN and that the co-expression of PTEN and ANXA2, but not ANXA2 Cys-8-Ala mutant, inhibits AKT phosphorylation on Ser 473. These results indicate that ANXA2 is important for PTEN regulation within the PI3K\/AKT signaling cascade. Furthermore, we also reveal that ANXA2 inversely regulates the expression of the peroxidase, peroxiredoxin 2, in a reactive oxygen species dependent manner.<\/jats:p>","DOI":"10.3390\/cancers11040492","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T11:54:52Z","timestamp":1554724492000},"page":"492","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Annexin A2 Regulates AKT Upon H2O2-Dependent Signaling Activation in Cancer Cells"],"prefix":"10.3390","volume":"11","author":[{"given":"St\u00e9phanie Anais","family":"Castaldo","sequence":"first","affiliation":[{"name":"Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal"}]},{"given":"Tom","family":"Ajime","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal"}]},{"given":"Gisela","family":"Serr\u00e3o","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal"}]},{"given":"F\u00e1bio","family":"Anast\u00e1cio","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7947-2681","authenticated-orcid":false,"given":"Joana Teixeira","family":"Rosa","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0179-2551","authenticated-orcid":false,"given":"Carman Anthony","family":"Giacomantonio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada"}]},{"given":"Alison","family":"Howarth","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Centre of Excellence, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, PO1 2DT Portsmouth, UK"}]},{"given":"Richard","family":"Hill","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal"},{"name":"Brain Tumour Research Centre of Excellence, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, PO1 2DT Portsmouth, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4856-3908","authenticated-orcid":false,"given":"Patr\u00edcia Alexandra","family":"Madureira","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal"},{"name":"Brain Tumour Research Centre of Excellence, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, PO1 2DT Portsmouth, UK"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.18632\/oncotarget.375","article-title":"Annexin A2 is a novel Cellular Redox Regulatory Protein involved in Tumorigenesis","volume":"2","author":"Madureira","year":"2011","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molcel.2007.03.016","article-title":"Hydrogen Peroxide Sensing and Signaling","volume":"26","author":"Veal","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1126\/science.1130481","article-title":"H2O2, a necessary evil for cell signaling","volume":"312","author":"Rhee","year":"2006","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3568","DOI":"10.3390\/ijms14023568","article-title":"Annexin A2: The importance of being redox sensitive","volume":"14","author":"Madureira","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.4161\/oxim.3.1.10095","article-title":"Redox regulation in cancer: A double-edged sword with therapeutic potential","volume":"3","author":"Acharya","year":"2010","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.cellsig.2012.01.008","article-title":"Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling","volume":"24","author":"Ray","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7709","DOI":"10.1016\/S0021-9258(19)38983-5","article-title":"Epidermal growth factor","volume":"265","author":"Carpenter","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0962-8924(02)00009-0","article-title":"Computational modeling of the EGF-receptor system: A paradigm for systems biology","volume":"13","author":"Wiley","year":"2003","journal-title":"Trends Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2005.0010","DOI":"10.1038\/msb4100014","article-title":"A comprehensive pathway map of epidermal growth factor receptor signaling","volume":"1","author":"Oda","year":"2005","journal-title":"Mol. Syst. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3109\/10715761003667554","article-title":"Reactive oxygen species in cancer","volume":"44","author":"Liou","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm2438","article-title":"Ras oncogenes: Split personalities","volume":"9","author":"Karnoub","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1182\/blood-2012-05-378596","article-title":"Targeting oncogenic Ras signaling in hematologic malignancies","volume":"120","author":"Ward","year":"2012","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1093\/emboj\/19.11.2393","article-title":"Signaling from Ras to Rac and beyond: Not just a matter of GEFs","volume":"19","author":"Scita","year":"2000","journal-title":"EMBO J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8413032","DOI":"10.1155\/2016\/8413032","article-title":"The Tumorigenic Roles of the Cellular REDOX Regulatory Systems","volume":"2016","author":"Castaldo","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Madureira, P.A., Hill, R., Lee, P.W.K., and Waisman, D.M. (2012). Genotoxic agents promote the nuclear accumulation of annexin A2: Role of annexin A2 in mitigating DNA damage. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050591"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"353687","DOI":"10.1155\/2012\/353687","article-title":"The biochemistry and regulation of S100A10: A multifunctional plasminogen receptor involved in oncogenesis","volume":"2012","author":"Madureira","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4789","DOI":"10.1182\/blood-2011-06-334672","article-title":"The role of the annexin A2 heterotetramer in vascular fibrinolysis","volume":"118","author":"Madureira","year":"2011","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.1093\/emboj\/cdg513","article-title":"Redox regulation of PI 3-kinase signalling via inactivation of PTEN","volume":"22","author":"Leslie","year":"2003","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/j.1460-2075.1983.tb01424.x","article-title":"A cellular protein phosphorylated by the avian sarcoma virus transforming gene product is associated with ribonucleoprotein particles","volume":"2","author":"Arrigo","year":"1983","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1089\/ars.2010.3393","article-title":"Multiple functions of peroxiredoxins: Peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones","volume":"15","author":"Rhee","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1152\/physrev.00030.2001","article-title":"Annexins: From structure to function","volume":"82","author":"Gerke","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"21839","DOI":"10.1016\/S0021-9258(19)36688-8","article-title":"Calcium-activated potassium transport and high molecular weight forms of calpromotin","volume":"267","author":"Plishker","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1083\/jcb.150.5.1113","article-title":"Annexins in cell membrane dynamics. Ca(2+)-regulated association of lipid microdomains","volume":"150","author":"Babiychuk","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18964","DOI":"10.1016\/S0021-9258(18)55157-7","article-title":"Reconstitution of Ca(2+)-dependent K+ transport in erythrocyte membrane vesicles requires a cytoplasmic protein","volume":"266","author":"Moore","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/0006-291X(90)91923-G","article-title":"Purification and measurement of calpromotin, the cytoplasmic protein which activates calcium-dependent potassium transport","volume":"166","author":"Moore","year":"1990","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8394","DOI":"10.1074\/jbc.M110.179416","article-title":"Peroxiredoxin II restrains DNA damage-induced death in cancer cells by positively regulating JNK-dependent DNA repair","volume":"286","author":"Lee","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1038\/emboj.2009.101","article-title":"Prdx1 inhibits tumorigenesis via regulating PTEN\/AKT activity","volume":"28","author":"Cao","year":"2009","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1126\/science.1080405","article-title":"Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling","volume":"300","author":"Wood","year":"2003","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"179","DOI":"10.18388\/abp.2010_2392","article-title":"Induction of CMV-1 promoter by 4-hydroxy-2-nonenal in human embryonic kidney cells","volume":"57","author":"Jaganjac","year":"2010","journal-title":"Acta Biochim. Pol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/4\/492\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:43:30Z","timestamp":1760186610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/4\/492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,7]]},"references-count":30,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["cancers11040492"],"URL":"https:\/\/doi.org\/10.3390\/cancers11040492","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2019,4,7]]}}}