Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle
Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle
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DOI：
10.1111/j.1742-4658.2009.07117.x
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发表时间：
2009-08-01
期刊：
影响因子：
5.4
通讯作者：
Kholodenko, Boris N.
中科院分区：
文献类型：
--
作者：
Kaimachnikov, Nikolai P.;Kholodenko, Boris N.
src家族激酶（SFKs）在生长因子信号传导、有丝分裂、细胞运动和侵袭性中发挥关键作用。在其基础状态下，sfk保持封闭的自抑制构象，其中Src同源2结构域与c端抑制性磷酸酪氨酸相互作用。激活包括抑制磷酸酪氨酸的去磷酸化，随后是激活环中特定酪氨酸残基的分子间自磷酸化。SFK激活的时空动态控制着细胞行为，但这些动态在很大程度上仍未被研究。在本研究中，我们发现Src激活/失活周期的基本特性可以带来复杂的信号动力学，包括振荡、切换和可兴奋行为。这些复杂的动态不需要强加的外部反馈回路，并且发生在Src抑制剂和激活剂的持续活动中，例如c端Src激酶和受体型蛋白酪氨酸磷酸酶。我们证明c端Src激酶和受体型蛋白酪氨酸磷酸酶的过表达或同时过表达可以分别将Src反应模式转化为振荡或双稳态反应。同样，Src过表达导致Src活性失调，促进持续的自我延续振荡。不同类型的反应可以允许sfk触发不同的细胞命运决定，其中细胞结果由刺激阈值和历史决定。我们的数学模型有助于理解令人困惑的实验观察结果，并提出了可以通过实验测试sfk这些不同动力学行为的条件。
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.