{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:59:53Z","timestamp":1790308793214,"version":"4.1.0"},"reference-count":107,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T00:00:00Z","timestamp":1715126400000},"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>Stress is a common denominator of complex disorders and the FK-506 binding protein (FKBP)51 plays a central role in stress. Hence, it is not surprising that multiple studies imply the involvement of the FKBP51 protein and\/or its coding gene, FKBP5, in complex disorders. This review summarizes such reports concentrating on three disorder clusters\u2014neuropsychiatric, cancer, and type 2 diabetes mellitus (T2DM). We also attempt to point to potential mechanisms suggested to mediate the effect of FKBP5\/FKBP51 on these disorders. Neuropsychiatric diseases considered in this paper include (i) Huntington\u2019s disease for which increased autophagic cellular clearance mechanisms related to decreased FKBP51 protein levels or activity is discussed, Alzheimer\u2019s disease for which increased FKBP51 activity has been shown to induce Tau phosphorylation and aggregation, and Parkinson\u2019s disease in the context of which FKBP12 is mentioned; and (ii) mental disorders, for which significant association with the single nucleotide polymorphism (SNP) rs1360780 of FKBP5 intron 7 along with decreased DNA methylation were revealed. Since cancer is a large group of diseases that can start in almost any organ or tissue of the body, FKBP51\u2019s role depends on the tissue type and differences among pathways expressed in those tumors. The FKBP51\u2013heat-shock protein-(Hsp)90\u2013p23 super-chaperone complex might function as an oncogene or as a tumor suppressor by downregulating the serine\/threonine protein kinase (AKt) pathway. In T2DM, two potential pathways for the involvement of FKBP51 are highlighted as affecting the pathogenesis of the disease\u2014the peroxisome proliferator-activated receptor-\u03b3 (PPAR\u03b3) and AKt.<\/jats:p>","DOI":"10.3390\/cells13100801","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T13:20:24Z","timestamp":1715174424000},"page":"801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The Role of FKBPs in Complex Disorders: Neuropsychiatric Diseases, Cancer, and Type 2 Diabetes Mellitus"],"prefix":"10.3390","volume":"13","author":[{"given":"Galila","family":"Agam","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, The Zlotowski Center for Neuroscience and Zelman Center\u2014The School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayan","family":"Atawna","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, The Zlotowski Center for Neuroscience and Zelman Center\u2014The School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odeya","family":"Damri","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, The Zlotowski Center for Neuroscience and Zelman Center\u2014The School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abed N.","family":"Azab","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, The Zlotowski Center for Neuroscience and Zelman Center\u2014The School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"},{"name":"Department of Nursing, School for Community Health Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/341758a0","article-title":"A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase","volume":"341","author":"Harding","year":"1989","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/341755a0","article-title":"A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin","volume":"341","author":"Siekierka","year":"1989","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.1016\/S0021-9258(19)39693-0","article-title":"Purification of unactivated progesterone receptor and identification of novel receptor-associated proteins","volume":"265","author":"Smith","year":"1990","journal-title":"J. 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