{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T23:06:54Z","timestamp":1778886414300,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T00:00:00Z","timestamp":1672185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014NextGenerationEU","award":["PE00000003"],"award-info":[{"award-number":["PE00000003"]}]},{"name":"European Union\u2014NextGenerationEU","award":["D93C22000890001"],"award-info":[{"award-number":["D93C22000890001"]}]},{"name":"Italian Ministry of University and Research","award":["PE00000003"],"award-info":[{"award-number":["PE00000003"]}]},{"name":"Italian Ministry of University and Research","award":["D93C22000890001"],"award-info":[{"award-number":["D93C22000890001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background &amp; Aims: Celiac disease (CeD) is an immune-mediated enteropathy triggered in genetically susceptible (HLA-DQ2\/8) individuals by a group of wheat proteins and related prolamins from cereals. The celiac intestine is characterized by an inversion of the differentiation\/proliferation program of the enterocytes, with an increase in the proliferative compartment and crypt hyperplasia, which are the mechanisms that regulate the increased proliferation in CeD that arenot completely understood.The aim of this study is to understand the role of Protein Tyrosine Phosphatase Receptor Type K (PTPRK), a nodal phosphatase that regulates EGFR activation in the proliferation of the enterocytes from CeD biopsies and organoids. Methods: The levels of PTPRK were evaluated by RT PCR, western blot (WB) and immunofluorescence techniques in intestinal biopsies and organoids from CeD patients and controls. Additionally, pEGFR and pERK were evaluated by WB and proliferation by BrdU incorporation. PTPRK si-RNA was silenced in CTR organoids and was overexpressed in CeD organoids. Results: PTPRK was reduced in Gluten Containing Diet\u2013Celiac Disease (GCD\u2013CeD) and Potential-Celiac Disease(Pot-CeD) biopsies (p &lt; 0.01\u2013p &lt; 0.05) whereas pEGFR (p &lt; 0.01 p &lt; 0.01), pERK (p &lt; 0.01 p &lt; 0.01) and proliferation were increased. (p &lt; 0.05 p &lt; 0.05) respect to the controls.The CeD organoids reproduced these same alterations. Silencing of PTPRK in CTR organoids increased pEGFR, pERK and proliferation. The overexpression of PTPRK in CeD organoids reduced pEGFR, pERK and proliferation. Conclusions: modulation of PTPRK levels can reduce or increase pEGFR, pERK and proliferation in CeD or CTR organoids, respectively. The CeD organoids can be a good model to study the mechanisms of the disease.<\/jats:p>","DOI":"10.3390\/cells12010115","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T05:28:24Z","timestamp":1672205304000},"page":"115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["PTPRK, an EGFR Phosphatase, Is Decreased in CeD Biopsies and Intestinal Organoids"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2569-4606","authenticated-orcid":false,"given":"Merlin","family":"Nanayakkara","sequence":"first","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Bellomo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Furone","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariantonia","family":"Maglio","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Marano","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuliana","family":"Lania","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monia","family":"Porpora","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvatore","family":"Auricchio","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-4917","authenticated-orcid":false,"given":"Maria Vittoria","family":"Barone","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"},{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barone, M.V., Auricchio, R., Nanayakkara, M., Greco, L., Troncone, R., and Auricchio, S. (2022). Pivotal Role of Inflammation in Celiac Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137177"},{"key":"ref_2","first-page":"667","article-title":"Time\/dose responses of coeliac mucosae to graded oral challenges with Frazer\u2019s fraction III of gliadin","volume":"4","author":"Marsh","year":"1992","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1136\/gut.34.12.1740-a","article-title":"Clinical and pathological spectrum of coeliac disease","volume":"34","author":"Mulder","year":"1993","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0950-3528(95)90032-2","article-title":"Morphology of the mucosal lesion in gluten sensitivity","volume":"9","author":"Marsh","year":"1995","journal-title":"Baillieres Clin. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20518","DOI":"10.3390\/ijms151120518","article-title":"Gliadin peptides as triggers of the proliferative and stress\/innate immune response of the celiac small intestinal mucosa","volume":"15","author":"Barone","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1365-2249.2007.03500.x","article-title":"Gluten affects epithelial differentiation-associated genes in small intestinal mucosa of coeliac patients","volume":"150","author":"Kainulainen","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Nanayakkara, M., Lania, G., Maglio, M., Kosova, R., Sarno, M., Gaito, A., Discepolo, V., Troncone, R., Auricchio, S., and Auricchio, R. (2013). Enterocyte proliferation and signaling are constitutively altered in celiac disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076006"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s42003-019-0443-1","article-title":"Constitutive alterations in vesicular trafficking increase the sensitivity of cells from celiac disease patients to gliadin","volume":"2","author":"Lania","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/bs.ircmb.2020.10.003","article-title":"The gliadin p31-43 peptide: Inducer of multiple proinflammatory effects","volume":"358","author":"Chirdo","year":"2021","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Barone, M.V., Zanzi, D., Maglio, M., Nanayakkara, M., Santagata, S., Lania, G., Miele, E., Ribecco, M.T., Maurano, F., and Auricchio, R. (2011). Gliadin-mediated proliferation and innate immune activation in celiac disease are due to alterations in vesicular trafficking. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017039"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Barone, M.V., Nanayakkara, M., Paolella, G., Maglio, M., Vitale, V., Troiano, R., Ribecco, M.T., Lania, G., Zanzi, D., and Santagata, S. (2010). Gliadin peptide P31-43 localises to endocytic vesicles and interferes with their maturation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012246"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Taavela, J., Viiri, K., Popp, A., Oittinen, M., Dotsenko, V., Per\u00e4aho, M., Staff, S., Sarin, J., Leon, F., and M\u00e4ki, M. (2019). Histological, immunohistochemical and mRNA gene expression responses in coeliac disease patients challenged with gluten using PAXgene fixed paraffin-embedded duodenal biopsies. BMC Gastroenterol., 19.","DOI":"10.1186\/s12876-019-1089-7"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1136\/gut.2005.086637","article-title":"Growth factor-like activity of gliadin, an alimentary protein: Implications for coeliac disease","volume":"56","author":"Barone","year":"2007","journal-title":"Gut"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Araya, R.E., Jury, J., Bondar, C., Verdu, E.F., and Chirdo, F.G. (2014). Intraluminal administration of poly I:C causes an enteropathy that is exacerbated by administration of oral dietary antigen. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099236"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"G40","DOI":"10.1152\/ajpgi.00435.2015","article-title":"Mechanisms of innate immune activation by gluten peptide p31-43 in mice","volume":"311","author":"Araya","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1146\/annurev-immunol-040210-092915","article-title":"Integration of genetic and immunological insights into a model of celiac disease pathogenesis","volume":"29","author":"Abadie","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1093\/hmg\/ddu453","article-title":"Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels","volume":"24","author":"Kumar","year":"2015","journal-title":"Hum. Mol. Genet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1093\/hmg\/ddt619","article-title":"Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant","volume":"23","author":"Almeida","year":"2014","journal-title":"Hum. Mol. Genet"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nanayakkara, M., Kosova, R., Lania, G., Sarno, M., Gaito, A., Galatola, M., Greco, L., Cuomo, M., Troncone, R., and Auricchio, S. (2013). A celiac cellular phenotype, with altered LPP sub-cellular distribution, is inducible in controls by the toxic gliadin peptide P31-43. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079763"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1593\/tlo.09112","article-title":"Cell Adhesion and Transcriptional Activity\u2014Defining the Role of the Novel Protooncogene LPP","volume":"2","author":"Grunewald","year":"2009","journal-title":"Transl. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Discepolo, V., Lania, G., Ten Eikelder, M.L.G., Nanayakkara, M., Sepe, L., Tufano, R., Troncone, R., Auricchio, S., Auricchio, R., and Paolella, G. (2021). Pediatric Celiac Disease Patients Show Alterations of Dendritic Cell Shape and Actin Rearrangement. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052708"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Fearnley, G.W., Young, K.A., Edgar, J.R., Antrobus, R., Hay, I.M., Liang, W.C., Martinez-Martin, N., Lin, W., Deane, J.E., and Sharpe, H.J. (2019). The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell-cell adhesion. Elife, 8.","DOI":"10.7554\/eLife.44597"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/ejhg.2013.136","article-title":"THEMIS and PTPRK in celiac intestinal mucosa: Coexpression in disease and after in vitro gliadin challenge","volume":"22","author":"Bondar","year":"2014","journal-title":"Eur. J. Hum. Genet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0092-8674(00)81357-4","article-title":"From form to function: Signaling by protein tyrosine phosphatases","volume":"87","author":"Tonks","year":"1996","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0065-2571(98)00014-4","article-title":"Cell signaling by protein tyrosine phosphorylation","volume":"39","author":"Fischer","year":"1999","journal-title":"Adv. Enzyme Regul."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"42694","DOI":"10.1074\/jbc.M507722200","article-title":"Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function","volume":"280","author":"Xu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Porpora, M., Conte, M., Lania, G., Bellomo, C., Rapacciuolo, L., Chirdo, F.G., Auricchio, R., Troncone, R., Auricchio, S., and Barone, M.V. (2022). Inflammation Is Present, Persistent and More Sensitive to Proinflammatory Triggers in Celiac Disease Enterocytes. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23041973"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.3945\/ajcn.112.054544","article-title":"An undigested gliadin peptide activates innate immunity and proliferative signaling in enterocytes: The role in celiac disease","volume":"98","author":"Nanayakkara","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3791","DOI":"10.1038\/onc.2014.312","article-title":"Protein tyrosine phosphatase PTPN3 inhibits lung cancer cell proliferation and migration by promoting EGFR endocytic degradation","volume":"34","author":"Li","year":"2015","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.3389\/fimmu.2018.02504","article-title":"Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease","volume":"9","author":"Pike","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1091\/mbc.E14-12-1591","article-title":"Notch and TGF-\u03b2 pathways cooperatively regulate receptor protein tyrosine phosphatase-\u03ba (PTPRK) gene expression in human primary keratinocytes","volume":"26","author":"Xu","year":"2015","journal-title":"Mol. Biol. Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/115\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:53:32Z","timestamp":1760147612000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,28]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12010115"],"URL":"https:\/\/doi.org\/10.3390\/cells12010115","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,28]]}}}