The proliferation of mast cells (MCs) plays a crucial role in either physiological or pathological progression of human physical. C-Kit-mediated signaling pathway has been confirmed to play a key role in MCs proliferation, and the regulatory mechanisms of C-Kit-mediated MCs proliferation need to be further explored. Our previous study found that protein 4.1R could negatively regulate T cell receptor (TCR) mediated signal pathways in CD4⁺ T cells. Little is known about the function of 4.1R in C-Kit-mediated proliferation of MCs. In this study, P815-4.1R^-/- cells were constructed by using CRISPR/Cas9 technique. Lack of 4.1R significantly enhanced P815 cells proliferation by accelerating the progression of cell cycle. 4.1R could also significantly alleviate the clinical symptoms of systemic mastocytosis (SM) and improve the overall survival of SM mice. Further study showed that 4.1R could interact directly with C-Kit to inhibit the activation of C-Kit-mediated Ras-Raf-MAPKs and PI3K-AKT signal pathways. Taken together, our findings demonstrate that protein 4.1R, a novel negative regulator, negatively regulates MCs proliferation by inhibiting C-Kit-mediated signal transduction, which maybe provide a potential target to the prevention and treatment of abnormal MCs proliferation-related diseases.

肥大细胞（MC）的增殖在人体生理或病理过程中起着至关重要的作用。 C-Kit介导的信号通路已被证实在MCs增殖中发挥关键作用，C-Kit介导的MCs增殖的调控机制有待进一步探讨。我们之前的研究发现，蛋白4.1R可以负向调节CD4 ⁺ T细胞中T细胞受体（TCR）介导的信号通路。关于 4.1R 在 C-Kit 介导的 MC 增殖中的功能知之甚少。本研究利用CRISPR/Cas9技术构建P815-4.1R ^-/-细胞。缺乏 4.1R 会加速细胞周期的进展，从而显着增强 P815 细胞的增殖。 4.1R还可以显着缓解系统性肥大细胞增多症（SM）的临床症状并提高SM小鼠的总体生存率。进一步研究表明，4.1R可以直接与C-Kit相互作用，抑制C-Kit介导的Ras-Raf-MAPKs和PI3K-AKT信号通路的激活。综上所述，我们的研究结果表明，蛋白4.1R是一种新型负调节因子，通过抑制C-Kit介导的信号转导来负调节MCs增殖，这可能为预防和治疗异常MCs增殖相关疾病提供潜在靶点。