Junior Research Group Pathoproteomics, Competence Center Functional Genomics, University of Greifswald Greifswald, Germany.
Front Cell Dev Biol. 2016 Mar 30;4:21. doi: 10.3389/fcell.2016.00021. eCollection 2016.
Macrophages represent the primary human host response to pathogen infection and link the immediate defense to the adaptive immune system. Mature tissue macrophages convert from circulating monocyte precursor cells by terminal differentiation in a process that is not fully understood. Here, we analyzed the protein kinases of the human monocytic cell line THP-1 before and after induction of macrophage differentiation by using kinomics and phosphoproteomics. When comparing the macrophage-like state with the monocytic precursor, 50% of the kinome was altered in expression and even 71% of covered kinase phosphorylation sites were affected. Kinome rearrangements are for example characterized by a shift of overrepresented cyclin-dependent kinases associated with cell cycle control in monocytes to calmodulin-dependent kinases and kinases involved in proinflammatory signaling. Eventually, we show that monocyte-to-macrophage differentiation is associated with major rewiring of mitogen-activated protein kinase signaling networks and demonstrate that protein kinase MAP3K7 (TAK1) acts as the key signaling hub in bacterial killing, chemokine production and differentiation. Our study proves the fundamental role of protein kinases and cellular signaling as major drivers of macrophage differentiation and function. The finding that MAP3K7 is central to macrophage function suggests MAP3K7 and its networking partners as promising targets in host-directed therapy for macrophage-associated disease.
巨噬细胞代表了人体对病原体感染的主要宿主反应，并将即时防御与适应性免疫系统联系起来。成熟的组织巨噬细胞通过终末分化从循环单核细胞前体细胞转化而来，这个过程尚未完全了解。在这里，我们使用激酶组学和磷酸化蛋白质组学分析了人单核细胞系 THP-1 在诱导巨噬细胞分化前后的蛋白激酶。当将巨噬细胞样状态与单核细胞前体进行比较时，激酶组的 50%表达发生改变，甚至覆盖的激酶磷酸化位点的 71%也受到影响。激酶组的重排例如表现为与单核细胞中细胞周期控制相关的过表达周期蛋白依赖性激酶向钙调蛋白依赖性激酶和参与促炎信号的激酶的转移。最终，我们表明单核细胞向巨噬细胞分化与丝裂原活化蛋白激酶信号网络的主要重排有关，并证明蛋白激酶 MAP3K7（TAK1）在细菌杀伤、趋化因子产生和分化中作为关键信号枢纽发挥作用。我们的研究证明了蛋白激酶和细胞信号作为巨噬细胞分化和功能的主要驱动因素的基本作用。MAP3K7 是巨噬细胞功能的核心这一发现表明 MAP3K7 及其网络伙伴作为针对与巨噬细胞相关疾病的宿主定向治疗的有希望的靶点。
