LCK 介导的 RIPK3 激活通过调节 PP2A-ERK 轴控制双阳性胸腺细胞增殖和抑制胸腺淋巴瘤,Advanced Science

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LCK 介导的 RIPK3 激活通过调节 PP2A-ERK 轴控制双阳性胸腺细胞增殖和抑制胸腺淋巴瘤
Advanced Science ( IF 14.3 ) Pub Date : 2022-09-25 , DOI: 10.1002/advs.202204522
Sung-Min Hwang _{1,

2} , Yu-Jin Ha _{1,

3} , Gi-Bang Koo _{1,

3} , Hyun-Jin Noh _{1,

3} , A-Yeon Lee _{1,

3} , Byeong-Ju Kim _{1,

3} , Sun Mi Hong ₁ , Michael J Morgan ₄ , Seong-Il Eyun ₅ , Dakeun Lee ₆ , Jae-Seok Roe ₇ , Youngsoo Lee ₈ , You-Sun Kim _{1,

3}

Affiliation

受体相互作用蛋白激酶 3 (RIPK3) 是坏死性细胞死亡的主要调节因子。RIPK3 表达通常在各种癌细胞中沉默，这表明它可能具有肿瘤抑制特性。然而，RIPK3 负向调节癌症发展和进展的确切机制仍不清楚。该报告表明 RIPK3 可作为 CD4 ⁺ CD8 ⁺双阳性 (DP) 胸腺细胞稳态增殖的有效调节剂。RIPK3 缺陷型 DP 胸腺细胞的异常增殖独立于 RIPK3 在坏死性凋亡（MLKL 激活的上游）中的众所周知的作用，并且与偶然的胸腺肿块相关，可能是胸腺增生。此外，Ripk3在N-乙基-N-亚硝基脲 (ENU) 诱导的肿瘤模型中，-null 小鼠的胸腺肿瘤形成增加，同时宿主存活率降低。此外，p53中的 RIPK3 缺陷-null 小鼠通过上调的细胞外信号调节激酶 (ERK) 信号促进胸腺淋巴瘤的发展，这与显着降低的存活率相关。从机制上讲，淋巴细胞特异性蛋白酪氨酸激酶 (LCK) 激活 RIPK3，进而导致蛋白磷酸酶 2 (PP2A) 的磷酸酶活性增加，从而抑制 DP 胸腺细胞中 ERK 的过度激活。总的来说，这些发现表明 RIPK3-PP2A-ERK 信号轴调节 DP 胸腺细胞稳态，并可能为改善胸腺淋巴瘤治疗提供潜在的治疗靶点。

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LCK-Mediated RIPK3 Activation Controls Double-Positive Thymocyte Proliferation and Restrains Thymic Lymphoma by Regulating the PP2A-ERK Axis

Receptor-interacting protein kinase 3 (RIPK3) is the primary regulator of necroptotic cell death. 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⁺CD8⁺ double-positive (DP) thymocytes. Abnormal proliferation of RIPK3-deficient DP thymocytes occurs independently of the well-known role for RIPK3 in necroptosis (upstream of MLKL activation), and is associated with an incidental thymic mass, likely thymic hyperplasia. In addition, Ripk3-null mice develop increased thymic tumor formation accompanied by reduced host survival in the context of an N-ethyl-N-nitrosourea (ENU)-induced tumor model. Moreover, RIPK3 deficiency in p53-null mice promotes thymic lymphoma development via upregulated extracellular signal-regulated kinase (ERK) signaling, which correlates with markedly reduced survival rates. Mechanistically, lymphocyte-specific protein tyrosine kinase (LCK) activates RIPK3, which in turn leads to increases in the phosphatase activity of protein phosphatase 2 (PP2A), thereby suppressing hyper-activation of ERK in DP thymocytes. Overall, these findings suggest that a RIPK3-PP2A-ERK signaling axis regulates DP thymocyte homeostasis and may provide a potential therapeutic target to improve thymic lymphoma therapies.

更新日期：2022-09-25

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