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RIPK3 expression is often silenced in various cancer cells, which suggests that it may have tumor suppressor properties. However, the exact mechanism by which RIPK3 negatively regulates cancer development and progression remains unclear. This report indicates that RIPK3 acts as a potent regulator of the homeostatic proliferation of CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> double\u2010positive (DP) thymocytes. Abnormal proliferation of RIPK3\u2010deficient DP thymocytes occurs independently of the well\u2010known role for RIPK3 in necroptosis (upstream of MLKL activation), and is associated with an incidental thymic mass, likely thymic hyperplasia. In addition, <jats:italic>Ripk3<\/jats:italic>\u2010null mice develop increased thymic tumor formation accompanied by reduced host survival in the context of an <jats:italic>N<\/jats:italic>\u2010ethyl\u2010<jats:italic>N<\/jats:italic>\u2010nitrosourea (ENU)\u2010induced tumor model. Moreover, RIPK3 deficiency in <jats:italic>p53<\/jats:italic>\u2010null mice promotes thymic lymphoma development via upregulated extracellular signal\u2010regulated kinase (ERK) signaling, which correlates with markedly reduced survival rates. Mechanistically, lymphocyte\u2010specific protein tyrosine kinase (LCK) activates RIPK3, which in turn leads to increases in the phosphatase activity of protein phosphatase 2 (PP2A), thereby suppressing hyper\u2010activation of ERK in DP thymocytes. Overall, these findings suggest that a RIPK3\u2010PP2A\u2010ERK signaling axis regulates DP thymocyte homeostasis and may provide a potential therapeutic target to improve thymic lymphoma therapies.<\/jats:p>","DOI":"10.1002\/advs.202204522","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T23:01:12Z","timestamp":1664146872000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["LCK\u2010Mediated RIPK3 Activation Controls Double\u2010Positive Thymocyte Proliferation and Restrains Thymic Lymphoma by Regulating the PP2A\u2010ERK Axis"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4868-147X","authenticated-orcid":false,"given":"Sung\u2010Min","family":"Hwang","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Ajou University School of Medicine  164 Worldcup\u2010ro, Yeongtong\u2010gu, Suwon Gyeonggi\u2010do 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