Cell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-induced intracellular JAK/STAT signalling is associated with severe inflammatory and proliferative diseases. Under physiological conditions JAK/STAT signalling is rigorously controlled and timely orchestrated by regulatory mechanisms such as expression of the feedback-inhibitor SOCS3 and activation of the protein-tyrosine phosphatase SHP2 (PTPN11). Interestingly, the function of negative regulators seems not to be restricted to controlling the strength and timely orchestration of IL-6-induced STAT3 activation. Exemplarily, SOCS3 increases robustness of late IL-6-induced STAT3 activation against heterogenous STAT3 expression and reduces the amount of information transferred through JAK/STAT signalling. Here we use multiplexed single-cell analyses and information theoretic approaches to clarify whether also SHP2 contributes to robustness of STAT3 activation and whether SHP2 affects the amount of information transferred through IL-6-induced JAK/STAT signalling. SHP2 increases robustness of both basal, cytokine-independent STAT3 activation and early IL-6-induced STAT3 activation against differential STAT3 expression. However, SHP2 does not affect robustness of late IL-6-induced STAT3 activation. In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells. These effects are independent of SHP2-dependent MAPK activation. In summary, the results of this study extend our knowledge of the functions of SHP2 in IL-6-induced JAK/STAT signalling. SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information. Plain English summary Cells within a multicellular organism communicate with each other to exchange information about the environment. Communication between cells is facilitated by soluble molecules that transmit information from one cell to the other. Cytokines such as interleukin-6 are important soluble mediators that are secreted when an organism is faced with infections or inflammation. Secreted cytokines bind to receptors within the membrane of their target cells. This binding induces activation of an intracellular cascade of reactions called signal transduction, which leads to cellular responses. An important example of intracellular signal transduction is JAK/STAT signalling. In healthy organisms signalling is controlled and timed by regulatory mechanisms, whose activation results in a controlled shutdown of signalling pathways. Interestingly, not all cells within an organism are identical. They differ in the amount of proteins involved in signal transduction, such as STAT3. These differences shape cellular communication and responses to intracellular signalling. Here, we show that an important negative regulatory protein called SHP2 (or PTPN11) is not only responsible for shutting down signalling, but also for steering signalling in heterogeneous cell populations. SHP2 increases robustness of STAT3 activation against variable STAT3 amounts in individual cells. Additionally, it increases the amount of information transferred through JAK/STAT signalling by increasing the dynamic range of pathway activation in heterogeneous cell populations. This is an amazing new function of negative regulatory proteins that contributes to communication in heterogeneous multicellular organisms in health and disease.

中文翻译：

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酪氨酸磷酸酶 SHP2 增加了 IL-6 诱导的 JAK/STAT 信号传导中的稳健性和信息传递

细胞间异质性是多细胞生物的固有特征，在包括细胞信号转导在内的所有生理和病理生理过程中都至关重要。细胞因子 IL-6 是促炎和抗炎过程的重要介质。失调的 IL-6 诱导的细胞内 JAK/STAT 信号传导与严重的炎症和增殖性疾病有关。在生理条件下，JAK/STAT 信号传导受到调节机制的严格控制和及时协调，例如反馈抑制剂 SOCS3 的表达和蛋白酪氨酸磷酸酶 SHP2 (PTPN11) 的激活。有趣的是，负调节剂的功能似乎并不局限于控制 IL-6 诱导的 STAT3 激活的强度和及时协调。例如，SOCS3 增加了晚期 IL-6 诱导的 STAT3 激活对异源 STAT3 表达的稳健性，并减少了通过 JAK/STAT 信号传导的信息量。在这里，我们使用多路复用单细胞分析和信息论方法来阐明 SHP2 是否也有助于 STAT3 激活的稳健性以及 SHP2 是否影响通过 IL-6 诱导的 JAK/STAT 信号传递的信息量。SHP2 增加了基础的、细胞因子非依赖性 STAT3 激活和早期 IL-6 诱导的 STAT3 激活对差异 STAT3 表达的稳健性。然而，SHP2 不影响晚期 IL-6 诱导的 STAT3 激活的稳健性。与 SOCS3 相比，SHP2 增加了通过 IL-6 诱导的 JAK/STAT 信号传递的信息量，可能是通过减少不依赖细胞因子的 STAT3 激活，从而增加细胞的敏感性。这些影响与 SHP2 依赖性 MAPK 激活无关。总之，本研究的结果扩展了我们对 SHP2 在 IL-6 诱导的 JAK/STAT 信号传导中的功能的认识。SHP2 不仅是基础和细胞因子诱导的 STAT3 活性的阻遏物，而且还确保信息的稳健性和传递。简单的英语摘要 多细胞生物中的细胞相互交流以交换有关环境的信息。可溶性分子促进细胞之间的交流，这些分子将信息从一个细胞传递到另一个细胞。白细胞介素 6 等细胞因子是重要的可溶性介质，当生物体面临感染或炎症时会分泌这些介质。分泌的细胞因子与其靶细胞膜内的受体结合。这种结合诱导激活称为信号转导的细胞内级联反应，从而导致细胞反应。细胞内信号转导的一个重要例子是 JAK/STAT 信号传导。在健康生物体中，信号传导由调节机制控制和定时，其激活导致信号通路的受控关闭。有趣的是，并非生物体内的所有细胞都是相同的。它们在参与信号转导的蛋白质数量上有所不同，例如 STAT3。这些差异塑造了细胞通讯和对细胞内信号的反应。在这里，我们展示了一种称为 SHP2（或 PTPN11）的重要负调节蛋白不仅负责关闭信号，还用于在异质细胞群中控制信号传导。SHP2 增加了 STAT3 激活对单个细胞中可变 STAT3 量的稳健性。此外，它通过增加异质细胞群中通路激活的动态范围来增加通过 JAK/STAT 信号传递的信息量。这是负调节蛋白的一个惊人的新功能，它有助于在健康和疾病中的异质多细胞生物中进行交流。