Shvartsman S Y, Hagan M P, Yacoub A, Dent P, Wiley H S, Lauffenburger D A
Department of Chemical Engineering, Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Am J Physiol Cell Physiol. 2002 Mar;282(3):C545-59. doi: 10.1152/ajpcell.00260.2001.
We describe a mechanism for context-dependent cell signaling mediated by autocrine loops with positive feedback. We demonstrate that the composition of the extracellular medium can critically influence the intracellular signaling dynamics induced by extracellular stimuli. Specifically, in the epidermal growth factor receptor (EGFR) system, amplitude and duration of mitogen-activated protein kinase (MAPK) activation are modulated by the positive-feedback loop formed by the EGFR, the Ras-MAPK signaling pathway, and a ligand-releasing protease. The signaling response to a transient input is short-lived when most of the released ligand is lost to the cellular microenvironment by diffusion and/or interaction with an extracellular ligand-binding component. In contrast, the response is prolonged or persistent in a cell that is efficient in recapturing the endogenous ligand. To study functional capabilities of autocrine loops, we have developed a mathematical model that accounts for ligand release, transport, binding, and intracellular signaling. We find that context-dependent signaling arises as a result of dynamic interaction between the parts of an autocrine loop. Using the model, we can directly interpret experimental observations on context-dependent responses of autocrine cells to ionizing radiation. In human carcinoma cells, MAPK signaling patterns induced by a short pulse of ionizing radiation can be transient or sustained, depending on cell type and composition of the extracellular medium. On the basis of our model, we propose that autocrine loops in this, and potentially other, growth factor and cytokine systems may serve as modules for context-dependent cell signaling.
我们描述了一种由具有正反馈的自分泌环介导的上下文依赖型细胞信号传导机制。我们证明细胞外培养基的组成可严重影响细胞外刺激诱导的细胞内信号传导动力学。具体而言，在表皮生长因子受体（EGFR）系统中，有丝分裂原激活蛋白激酶（MAPK）激活的幅度和持续时间由EGFR、Ras-MAPK信号通路和一种配体释放蛋白酶形成的正反馈环调节。当大多数释放的配体通过扩散和/或与细胞外配体结合成分相互作用而散失到细胞微环境中时，对瞬时输入的信号反应是短暂的。相反，在能够有效重新捕获内源性配体的细胞中，反应会延长或持续。为了研究自分泌环的功能能力，我们开发了一个数学模型，该模型考虑了配体的释放、运输、结合和细胞内信号传导。我们发现上下文依赖型信号传导是自分泌环各部分之间动态相互作用的结果。使用该模型，我们可以直接解释关于自分泌细胞对电离辐射的上下文依赖型反应的实验观察结果。在人类癌细胞中，电离辐射短脉冲诱导的MAPK信号模式可以是短暂的或持续的，这取决于细胞类型和细胞外培养基的组成。基于我们的模型，我们提出在这个以及可能的其他生长因子和细胞因子系统中的自分泌环可能作为上下文依赖型细胞信号传导的模块。
