{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:38:09Z","timestamp":1760236689193,"version":"build-2065373602"},"reference-count":17,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.<\/jats:p>","DOI":"10.3390\/cells10123545","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T09:02:19Z","timestamp":1639558939000},"page":"3545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease"],"prefix":"10.3390","volume":"10","author":[{"given":"Raisa","family":"Kraaijvanger","sequence":"first","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kees","family":"Seldenrijk","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, Pathology DNA, Department of Pathology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0439-2550","authenticated-orcid":false,"given":"Els","family":"Beijer","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Damen","sequence":"additional","affiliation":[{"name":"Pathology DNA, Department of Pathology, Jeroen Bosch Hospital, 5223 GZ \u2019s-Hertogenbosch, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0560-6207","authenticated-orcid":false,"given":"Jayne Louise","family":"Wilson","sequence":"additional","affiliation":[{"name":"Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-0797","authenticated-orcid":false,"given":"Thomas","family":"Weichhart","sequence":"additional","affiliation":[{"name":"Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan C.","family":"Grutters","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"},{"name":"Division of Hearth and Lungs, University Medical Centre, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Veltkamp","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Centre of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"},{"name":"Division of Hearth and Lungs, University Medical Centre, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR Signaling in Growth Control and Disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/ni.3655","article-title":"Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression","volume":"18","author":"Linke","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.canlet.2014.02.008","article-title":"Antagonistic role of natural compounds in mTOR-mediated metabolic reprogramming","volume":"356","author":"Cerella","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14056","DOI":"10.1074\/jbc.M700906200","article-title":"RAS\/ERK Signaling Promotes Site-specific Ribosomal Protein S6 Phosphorylation via RSK and Stimulates Cap-dependent Translation","volume":"282","author":"Roux","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev-med-050715-104245","article-title":"Lymphangioleiomyomatosis: A Monogenic Model of Malignancy","volume":"68","author":"Krymskaya","year":"2017","journal-title":"Annu. Rev. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1172\/JCI58709","article-title":"Lymphangioleiomyomatosis\u2014A wolf in sheep\u2019s clothing","volume":"122","author":"Henske","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cao, G.-D., Xu, X.-Y., Zhang, J.-W., Chen, B., and Xiong, M.-M. (2016). Phosphorylated Mammalian Target of Rapamycin p-mTOR Is a Favorable Prognostic Factor than mTOR in Gastric Cancer. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168085"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.lungcan.2011.06.012","article-title":"Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study","volume":"75","author":"Gately","year":"2012","journal-title":"Lung Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1164\/ajrccm.160.2.ats4-99","article-title":"Statement on Sarcoidosis","volume":"160","author":"Hunninghake","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1749-6632.1976.tb47010.x","article-title":"Immunologic components of granuloma formation. Epithelioid cells, giant cells, and sarcoidosis","volume":"278","author":"Spector","year":"1976","journal-title":"Ann. NY Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106294","DOI":"10.1016\/j.rmed.2020.106294","article-title":"High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis","volume":"177","author":"Pizzini","year":"2021","journal-title":"Respir. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"00486","DOI":"10.1183\/23120541.00486-2020","article-title":"Presence of Propionibacterium acnes in granulomas associates with a chronic disease course in Dutch sarcoidosis patients","volume":"7","author":"Beijer","year":"2021","journal-title":"ERJ Open Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Beijer, E., Seldenrijk, K., Meek, B., Damen, J., Quanjel, M.J.R., Grutters, J.C., and Veltkamp, M. (2021). Detection of Cutibacterium acnes in granulomas of patients with either hypersensitivity pneumonitis or vasculitis reveals that its presence is not unique for sarcoidosis. ERJ Open Res., 7.","DOI":"10.1183\/23120541.00930-2020"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1034\/j.1399-3003.1999.14d02.x","article-title":"ATS\/ERS\/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders","volume":"14","author":"Costabel","year":"1999","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7207","DOI":"10.1158\/1078-0432.CCR-09-1249","article-title":"Targeted Inhibition of Mammalian Target of Rapamycin Signaling Inhibits Tumorigenesis of Colorectal Cancer","volume":"15","author":"Gulhati","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_16","first-page":"56","article-title":"Defining the clinical outcome status (COS) in sarcoidosis: Results of WASOG Task Force","volume":"28","author":"Baughman","year":"2011","journal-title":"Sarcoidosis Vasc. Diffus. Lung Dis. Off. J. WASOG"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1128\/MCB.24.8.3112-3124.2004","article-title":"S6K1\u2212\/\u2212\/S6K2\u2212\/\u2212 Mice Exhibit Perinatal Lethality and Rapamycin-Sensitive 5\u2032-Terminal Oligopyrimidine mRNA Translation and Reveal a Mitogen-Activated Protein Kinase-Dependent S6 Kinase Pathway","volume":"24","author":"Pende","year":"2004","journal-title":"Mol. Cell Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3545\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:48:55Z","timestamp":1760168935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,15]]},"references-count":17,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123545"],"URL":"https:\/\/doi.org\/10.3390\/cells10123545","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2021,12,15]]}}}