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首页> 外文期刊>The FEBS journal >Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle
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Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle

机译：拨动开关，脉冲和振荡是Src激活/停用周期的固有属性

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Src-family kinases (SFKs) play a pivotal role in growth factor signaling, mitosis, cell motility and invasiveness. In their basal state, SFKs maintain a closed autoinhibited conformation, where the Src homology 2 domain interacts with an inhibitory phosphotyrosine in the C-terminus. Activation involves dephosphorylation of this inhibitory phosphotyrosine, followed by intermolecular autophosphorylation of a specific tyrosine residue in the activation loop. The spatiotemporal dynamics of SFK activation controls cell behavior, yet these dynamics remain largely uninvestigated. In the present study, we show that the basic properties of the Src activation/deactivation cycle can bring about complex signaling dynamics, including oscillations, toggle switches and excitable behavior. These intricate dynamics do not require imposed external feedback loops and occur at constant activities of Src inhibitors and activators, such as C-terminal Src kinase and receptor-type protein tyrosine phosphatases. We demonstrate that C-terminal Src kinase and receptor-type protein tyrosine phosphatase underexpression or their simultaneous overexpression can transform Src response patterns into oscillatory or bistable responses, respectively. Similarly, Src overexpression leads to dysregulation of Src activity, promoting sustained self-perpetuating oscillations. Distinct types of responses can allow SFKs to trigger different cell-fate decisions, where cellular outcomes are determined by the stimulation threshold and history. Our mathematical model helps to understand the puzzling experimental observations and suggests conditions where these different kinetic behaviors of SFKs can be tested experimentally.
机译：Src家族激酶（SFK）在生长因子信号传导，有丝分裂，细胞运动性和侵袭性中起关键作用。 SFKs在其基础状态下保持封闭的自抑制构象，其中Src同源性2结构域与C端的抑制性磷酸酪氨酸相互作用。活化涉及该抑制性磷酸酪氨酸的去磷酸化，然后是活化环中特定酪氨酸残基的分子间自磷酸化。 SFK激活的时空动力学控制细胞的行为，但这些动力学很大程度上尚未调查。在本研究中，我们表明Src激活/去激活周期的基本属性可以带来复杂的信号动力学，包括振荡，拨动开关和兴奋性行为。这些复杂的动力学不需要施加外部反馈回路，并且可以在Src抑制剂和激活剂（例如C末端Src激酶和受体型蛋白酪氨酸磷酸酶）的恒定活性下发生。我们证明，C末端Src激酶和受体型蛋白酪氨酸磷酸酶表达不足或它们同时过度表达可以分别将Src反应模式转变为振荡或双稳态反应。同样，Src过表达会导致Src活动失调，从而促进持续的自我延续振荡。不同类型的响应可以使SFK触发不同的细胞命运决定，其中细胞结果由刺激阈值和病史决定。我们的数学模型有助于理解令人费解的实验观察结果，并提出可以通过实验测试SFK这些不同动力学行为的条件。

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