Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28/Pfälzer Platz, 39106, Magdeburg, Germany.
Institute of Molecular Medicine, Charles Tanford Protein Research Center, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 3a, 06120, Halle (Saale), Germany.
Cell Commun Signal. 2019 Oct 24;17(1):135. doi: 10.1186/s12964-019-0451-2.
BACKGROUND: Cytokine-dependent activation of signalling pathways is tightly orchestrated. The spatiotemporal activation of signalling pathways dictates the specific physiological responses to cytokines. Dysregulated signalling accounts for neoplastic, developmental, and inflammatory diseases. Grb2-associated binder (Gab) family proteins are multi-site docking proteins, which expand cytokine-induced signal transduction in a spatial- and time-dependent manner by coordinating the recruitment of proteins involved in mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) and phosphatidyl-inositol-3-kinase (PI3K) signalling. Interaction of Gab family proteins with these signalling proteins determines strength, duration and localization of active signalling cascades. However, the underlying molecular mechanisms of signal orchestration by Gab family proteins in IL-6-induced signalling are only scarcely understood. METHODS: We performed kinetic analyses of interleukin-6 (IL-6)-induced MAPK activation and analysed downstream responses. We compared signalling in wild-type cells, Gab1 knock-out cells, those reconstituted to express Gab1 mutants, and cells expressing gp130 receptors or receptor mutants. RESULTS: Interleukin-6-induced MAPK pathway activation can be sub-divided into an early Gab1-independent and a subsequent Gab1-dependent phase. Early Gab1-independent MAPK activation is critical for the subsequent initiation of Gab1-dependent amplification of MAPK pathway activation and requires binding of SH2 domain-containing phosphatase 2 (SHP2) to the interleukin-6 receptor complex. Subsequent and coordinated recruitment of Grb2 and SHP2 to Gab1 is essential for Gab1-dependent amplification of IL-6-induced late MAPK pathway activation and subsequent gene expression. CONCLUSIONS: Overall, we elaborated the molecular requirements for Gab1-dependent, spatiotemporal orchestration of interleukin-6-dependent MAPK signalling. We discriminated IL-6-induced Gab1-independent, early activation of MAPK signalling and Gab1-dependent, sustained activation of MAPK signalling.
背景：细胞因子依赖的信号通路激活受到严格调控。信号通路的时空激活决定了细胞因子的特定生理反应。信号转导失调与肿瘤、发育和炎症性疾病有关。Grb2 相关结合蛋白（Gab）家族蛋白是多位点衔接蛋白，通过协调参与丝裂原激活蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）和磷酸肌醇-3-激酶（PI3K）信号的蛋白募集，以时空依赖的方式扩展细胞因子诱导的信号转导。Gab 家族蛋白与这些信号蛋白的相互作用决定了活性信号级联的强度、持续时间和定位。然而，Gab 家族蛋白在白细胞介素-6（IL-6）诱导的信号中协调信号的潜在分子机制仅知之甚少。
方法：我们进行了白细胞介素-6（IL-6）诱导的 MAPK 激活的动力学分析，并分析了下游反应。我们比较了野生型细胞、Gab1 敲除细胞、表达 Gab1 突变体的细胞、表达 gp130 受体或受体突变体的细胞中的信号。
结果：白细胞介素-6 诱导的 MAPK 通路激活可分为早期 Gab1 非依赖性和随后的 Gab1 依赖性阶段。早期 Gab1 非依赖性 MAPK 激活对于随后 Gab1 依赖性 MAPK 通路激活的放大的启动至关重要，并且需要 SH2 结构域含有磷酸酶 2（SHP2）与白细胞介素-6 受体复合物结合。Grb2 和 SHP2 随后协调募集到 Gab1 对于 Gab1 依赖性放大白细胞介素-6 诱导的晚期 MAPK 通路激活和随后的基因表达是必需的。
结论：总的来说，我们阐述了 Gab1 依赖性、时空协调白细胞介素-6 依赖性 MAPK 信号所必需的分子要求。我们区分了白细胞介素-6 诱导的 Gab1 非依赖性、早期 MAPK 信号激活和 Gab1 依赖性、持续的 MAPK 信号激活。
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