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Here, we present the first dual small molecule-gated ZAP70 signaling switch for the regulation of T cell activity. We show that when an analogue-sensitive ZAP70 allele is fused to the engineered ligand binding domain of the estrogen receptor, ERT2, its activity can be upregulated to an extent by a metabolite of an FDA-approved tamoxifen, 4-hydroxy-tamoxifen, and downregulated by an ATP analogue, 3-MB-PP1. The strength of early T cell signaling can also be modulated by varying the concentrations of activator and inhibitor, and the switch exhibits temporal control on the time scale of minutes. Interestingly, the switch has the ability to control CD69 and calcium levels in T cells but has limited capabilities in the regulation of downstream cytokine release, suggesting further investigation is needed before it can be implemented in adoptive T cell therapy.<\/jats:p>","DOI":"10.1021\/acssynbio.7b00394","type":"journal-article","created":{"date-parts":[[2018,3,28]],"date-time":"2018-03-28T14:46:27Z","timestamp":1522248387000},"page":"969-977","source":"Crossref","is-referenced-by-count":10,"title":["Engineering a Dual Small Molecule Gated ZAP70 Switch\nin T Cells"],"prefix":"10.1021","volume":"7","author":[{"given":"Nicole M. L.","family":"Wong","sequence":"first","affiliation":[{"name":"Boston University , , , ,","place":["Boston, Massachusetts, United States, 02215"]},{"name":"Boston University , , , ,","place":["Boston, Massachusetts, United States, 02215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-889X","authenticated-orcid":true,"given":"Wilson W.","family":"Wong","sequence":"additional","affiliation":[{"name":"Boston University , , , ,","place":["Boston, Massachusetts, United States, 02215"]},{"name":"Boston University , , , ,","place":["Boston, Massachusetts, United States, 02215"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,3,28]]},"reference":[{"key":"2026090223413456000_cit1","doi-asserted-by":"publisher","first-page":"224ra225","DOI":"10.1126\/scitranslmed.3008226","article-title":"Efficacy and toxicity management of 19\u201328z CAR\nT cell therapy in B cell acute lymphoblastic leukemia","volume":"6","author":"Davila","year":"2014","journal-title":"Sci. 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Oncol."},{"key":"2026090223413456000_cit3","doi-asserted-by":"publisher","first-page":"4099","DOI":"10.1182\/blood-2010-04-281931","article-title":"Eradication\nof B-lineage cells and regression of lymphoma in a patient treated\nwith autologous T cells genetically engineered to recognize CD19","volume":"116","author":"Kochenderfer","year":"2010","journal-title":"Blood"},{"key":"2026090223413456000_cit4","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/S0140-6736(14)61403-3","article-title":"T cells\nexpressing CD19 chimeric antigen receptors for acute lymphoblastic\nleukaemia in children and young adults: a phase 1 dose-escalation\ntrial","volume":"385","author":"Lee","year":"2015","journal-title":"Lancet"},{"key":"2026090223413456000_cit5","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1056\/NEJMoa1407222","article-title":"Chimeric\nantigen receptor T cells for sustained remissions in leukemia","volume":"371","author":"Maude","year":"2014","journal-title":"N. 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Rev."},{"key":"2026090223413456000_cit31","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1038\/ni.1955","article-title":"A genetically selective inhibitor demonstrates a function for the\nkinase Zap70 in regulatory T cells independent of its catalytic activity","volume":"11","author":"Au-Yeung","year":"2010","journal-title":"Nat. Immunol."},{"key":"2026090223413456000_cit32","doi-asserted-by":"publisher","first-page":"9166","DOI":"10.1073\/pnas.88.20.9166","article-title":"The zeta chain is associated\nwith a tyrosine kinase and upon T-cell antigen receptor stimulation\nassociates with ZAP-70, a 70-kDa tyrosine phosphoprotein","volume":"88","author":"Chan","year":"1991","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026090223413456000_cit33","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/0092-8674(92)90598-7","article-title":"ZAP-70: a 70 kd protein-tyrosine kinase that associates with the\nTCR zeta chain","volume":"71","author":"Chan","year":"1992","journal-title":"Cell"},{"key":"2026090223413456000_cit34","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1084\/jem.20070405","article-title":"Distinct roles for\nSyk and ZAP-70 during early thymocyte development","volume":"204","author":"Palacios","year":"2007","journal-title":"J. Exp. Med."},{"key":"2026090223413456000_cit35","doi-asserted-by":"publisher","first-page":"19641","DOI":"10.1074\/jbc.271.33.19641","article-title":"Phosphorylation of SLP-76 by the\nZAP-70 protein-tyrosine kinase is required for T-cell receptor function","volume":"271","author":"Bubeck Wardenburg","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2026090223413456000_cit36","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nri1414","article-title":"Transmembrane adaptor\nproteins: organizers of immunoreceptor signalling","volume":"4","author":"Horejsi","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"2026090223413456000_cit37","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nri1750","article-title":"SLP76 and SLP65: complex regulation\nof signalling in lymphocytes and beyond","volume":"6","author":"Koretzky","year":"2006","journal-title":"Nat.\nRev. Immunol."},{"key":"2026090223413456000_cit38","doi-asserted-by":"publisher","first-page":"a002279","DOI":"10.1101\/cshperspect.a002279","article-title":"ZAP-70: an\nessential kinase in T-cell signaling","volume":"2","author":"Wang","year":"2010","journal-title":"Cold Spring\nHarbor Perspect. Biol."},{"key":"2026090223413456000_cit39","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0092-8674(00)80901-0","article-title":"LAT: the\nZAP-70 tyrosine kinase substrate that links T cell receptor to cellular\nactivation","volume":"92","author":"Zhang","year":"1998","journal-title":"Cell"},{"key":"2026090223413456000_cit40","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1126\/science.8202713","article-title":"ZAP-70 deficiency\nin an autosomal recessive form of severe combined immunodeficiency","volume":"264","author":"Chan","year":"1994","journal-title":"Science"},{"key":"2026090223413456000_cit41","first-page":"310","article-title":"ZAP-70\nand defects of T-cell receptor signaling","volume":"35","author":"Elder","year":"1998","journal-title":"Semin.\nHematol."},{"key":"2026090223413456000_cit42","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1126\/science.8202712","article-title":"Human severe\ncombined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine\nkinase","volume":"264","author":"Elder","year":"1994","journal-title":"Science"},{"key":"2026090223413456000_cit43","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1128\/MCB.18.3.1388","article-title":"Genetic evidence for differential coupling of Syk family\nkinases to the T-cell receptor: reconstitution studies in a ZAP-70-deficient\nJurkat T-cell line","volume":"18","author":"Williams","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"2026090223413456000_cit44","doi-asserted-by":"publisher","first-page":"15419","DOI":"10.1074\/jbc.M709000200","article-title":"Inhibition of ZAP-70 kinase activity\nvia an analog-sensitive allele blocks T cell receptor and CD28 superagonist\nsignaling","volume":"283","author":"Levin","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2026090223413456000_cit45","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1084\/jem.20021698","article-title":"Restricting Zap70 expression\nto CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading\nmechanism controlling the completion of positive selection","volume":"197","author":"Liu","year":"2003","journal-title":"J. Exp. 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Biophys.\nActa, Biomembr."},{"key":"2026090223413456000_cit49","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1146\/annurev.immunol.19.1.497","article-title":"Calcium signaling mechanisms in T lymphocytes","volume":"19","author":"Lewis","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"2026090223413456000_cit50","doi-asserted-by":"publisher","first-page":"7137","DOI":"10.1128\/MCB.21.21.7137-7149.2001","article-title":"Zap-70-independent\nCa(2+) mobilization and Erk activation in Jurkat T cells in response\nto T-cell antigen receptor ligation","volume":"21","author":"Shan","year":"2001","journal-title":"Mol. Cell.\nBiol."},{"key":"2026090223413456000_cit51","doi-asserted-by":"publisher","first-page":"3942","DOI":"10.1021\/ja209933r","article-title":"Destabilizing domains\nderived from the human estrogen receptor","volume":"134","author":"Miyazaki","year":"2012","journal-title":"J.\nAm. Chem. 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Biol."},{"key":"2026090223413456000_cit55","doi-asserted-by":"crossref","first-page":"9873","DOI":"10.1128\/JVI.72.12.9873-9880.1998","article-title":"Self-inactivating\nlentivirus vector for safe and efficient in vivo gene delivery","volume":"72","author":"Zufferey","year":"1998","journal-title":"J. Virol."}],"container-title":["ACS Synthetic Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acssynbio.7b00394","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/asbcd6\/article-pdf\/7\/4\/969\/67117752\/acssynbio.7b00394.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/asbcd6\/article-pdf\/7\/4\/969\/67117752\/acssynbio.7b00394.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:41:37Z","timestamp":1788406897000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/asbcd6\/article\/7\/4\/969\/731059\/Engineering-a-Dual-Small-Molecule-Gated-ZAP70"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,28]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,3,28]]},"published-print":{"date-parts":[[2018,4,20]]}},"URL":"https:\/\/doi.org\/10.1021\/acssynbio.7b00394","relation":{},"ISSN":["2161-5063"],"issn-type":[{"value":"2161-5063","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,28]]}}}