In responses to activation of receptor tyrosine kinases (RTKs), crucial cell fate decisions depend on the duration and dynamics of ERK signaling. In PC12 cells, epidermal growth factor (EGF) induces transient ERK activation that leads to cell proliferation, whereas nerve growth factor (NGF) promotes sustained ERK activation and cell differentiation. These differences have typically been assumed to reflect distinct feedback mechanisms in the Raf-MEK-ERK signaling network, with the receptors themselves acting as simple upstream inputs. We failed to confirm the expected differences in feedback type when investigating transient versus sustained signaling downstream of the EGF receptor (EGFR) and NGF receptor (TrkA). Instead, we found that ERK signaling faithfully followed RTK dynamics when receptor signaling was modulated in different ways. EGFR activation kinetics, and consequently ERK signaling dynamics, were switched from transient to sustained when receptor internalization was inhibited with drugs or mutations, or when cells expressed a chimeric receptor likely to have impaired dimerization. In addition, EGFR and ERK signaling both became more sustained when substoichiometric levels of erlotinib were added to reduce duration of EGFR kinase activation. Our results argue that RTK activation kinetics play a crucial role in determining MAP kinase cascade signaling dynamics and cell fate decisions, and that signaling outcome can be modified by activating a given RTK in different ways.

为了响应受体酪氨酸激酶 (RTK) 的激活，关键的细胞命运决定取决于 ERK 信号传导的持续时间和动态。在 PC12 细胞中，表皮生长因子 (EGF) 诱导导致细胞增殖的瞬时 ERK 激活，而神经生长因子 (NGF) 促进持续的 ERK 激活和细胞分化。这些差异通常被认为反映了 Raf-MEK-ERK 信号网络中不同的反馈机制，受体本身充当简单的上游输入。在研究 EGF 受体 (EGFR) 和 NGF 受体 (TrkA) 下游的瞬时与持续信号传导时，我们未能确认反馈类型的预期差异。相反，我们发现当受体信号以不同方式调节时，ERK 信号忠实地遵循 RTK 动力学。当受体内化被药物或突变抑制时，或者当细胞表达可能已受损二聚化的嵌合受体时，EGFR 激活动力学，以及因此的 ERK 信号动力学，从瞬态转变为持续性。此外，当加入亚化学计量水平的厄洛替尼以减少 EGFR 激酶激活的持续时间时，EGFR 和 ERK 信号都变得更加持续。我们的结果表明，RTK 激活动力学在确定 MAP 激酶级联信号动力学和细胞命运决定方面起着至关重要的作用，并且可以通过以不同方式激活给定的 RTK 来改变信号转导结果。或当细胞表达可能已受损二聚化的嵌合受体时。此外，当加入亚化学计量水平的厄洛替尼以减少 EGFR 激酶激活的持续时间时，EGFR 和 ERK 信号都变得更加持续。我们的研究结果表明，RTK 激活动力学在确定 MAP 激酶级联信号动力学和细胞命运决定方面起着至关重要的作用，并且可以通过以不同方式激活给定的 RTK 来改变信号转导结果。或者当细胞表达可能已受损二聚化的嵌合受体时。此外，当加入亚化学计量水平的厄洛替尼以减少 EGFR 激酶激活的持续时间时，EGFR 和 ERK 信号传导都变得更加持续。我们的结果表明，RTK 激活动力学在确定 MAP 激酶级联信号动力学和细胞命运决定方面起着至关重要的作用，并且可以通过以不同方式激活给定的 RTK 来改变信号转导结果。