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Campus","award":["SCHM1586\/6-2"],"award-info":[{"award-number":["SCHM1586\/6-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Signaling via the TCR, which is initiated by the Src-family tyrosine kinase Lck, is crucial for the determination of cell fates in the thymus. Because of its pivotal role, ablation of Lck results in a profound block of T-cell development. Here, we show that, in addition to its well-known function in the initiation of TCR signaling, Lck also acts at a more downstream level. This novel function of Lck is determined by the tyrosine residue (Y192) located in its SH2 domain. Thymocytes from knock-in mice expressing a phosphomimetic Y192E mutant of Lck initiate TCR signaling upon CD3 cross-linking up to the level of PLC-\u03b31 phosphorylation. However, the activation of downstream pathways including Ca2+ influx and phosphorylation of Erk1\/2 are impaired. Accordingly, positive and negative selections are blocked in LckY192E knock-in mice. Collectively, our data indicate that Lck has a novel function downstream of PLC\u03b3-1 in the regulation of thymocyte differentiation and selection.<\/jats:p>","DOI":"10.3390\/ijms23137271","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:21:50Z","timestamp":1656634910000},"page":"7271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-\u03b31 and Thymic Selection"],"prefix":"10.3390","volume":"23","author":[{"given":"Matthias","family":"K\u00e4stle","sequence":"first","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Merten","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-7458","authenticated-orcid":false,"given":"Roland","family":"Hartig","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Plaza-Sirvent","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Department of Molecular Immunology, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-0419","authenticated-orcid":false,"given":"Ingo","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Department of Molecular Immunology, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Bommhardt","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Health Campus Immunology, Infectiology and Inflammation (GC-I3), Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4321-7405","authenticated-orcid":false,"given":"Burkhart","family":"Schraven","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Health Campus Immunology, Infectiology and Inflammation (GC-I3), Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Simeoni","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Health Campus Immunology, Infectiology and Inflammation (GC-I3), Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"},{"name":"Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nri798","article-title":"T-cell development and the CD4-CD8 lineage decision","volume":"2","author":"Germain","year":"2002","journal-title":"Nat. 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