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首页> 外文期刊>Molecular and Cellular Biology >Establishment of Extracellular Signal-Regulated Kinase 1/2 Bistability and Sustained Activation through Sprouty 2 and Its Relevance for Epithelial Function
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Establishment of Extracellular Signal-Regulated Kinase 1/2 Bistability and Sustained Activation through Sprouty 2 and Its Relevance for Epithelial Function

机译：细胞外信号调节激酶1/2双稳性和通过sprouty 2持续激活的建立及其与上皮功能的相关性

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Our objective was to establish an experimental model of a self-sustained and bistable extracellular signal-regulated kinase 1/2 (ERK1/2) signaling process. A single stimulation of cells with cytokines causes rapid ERK1/2 activation, which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase (JNK), p38, or STAT6. The ERK1/2 activation lasts for 3 to 7 days and depends upon a positive-feedback mechanism involving Sprouty 2. Overexpression of Sprouty 2 induces, and its genetic deletion abrogates, ERK1/2 bistability. Sprouty 2 directly activates Fyn kinase, which then induces ERK1/2 activation. A genome-wide microarray analysis shows that the bistable phospho-ERK1/2 (pERK1/2) does not induce a high level of gene transcription. This is due to its nuclear exclusion and compartmentalization to Rab5+ endosomes. Cells with sustained endosomal pERK1/2 manifest resistance against growth factor withdrawal-induced cell death. They are primed for heightened cytokine production. Epithelial cells from cases of human asthma and from a mouse model of chronic asthma manifest increased pERK1/2, which is associated with Rab5+ endosomes. The increase in pERK1/2 was associated with a simultaneous increase in Sprouty 2 expression in these tissues. Thus, we have developed a cellular model of sustained ERK1/2 activation, which may provide a mechanistic understanding of self-sustained biological processes in chronic illnesses such as asthma.
机译：我们的目标是建立一个自我维持和双稳态细胞外信号调节激酶1/2（ERK1 / 2）信号传导过程的实验模型。细胞因子对细胞的单次刺激会导致ERK1 / 2迅速激活，并在4小时内恢复到基线。重复刺激会导致ERK1 / 2持续激活，但不会激活Jun N末端蛋白激酶（JNK），p38或STAT6。 ERK1 / 2激活持续3到7天，并取决于涉及Sprouty 2的正反馈机制。Sprouty2的过表达诱导了ERK1 / 2的双稳态，并且其遗传缺失消除了ERK1 / 2的双稳性。 Sprouty 2直接激活Fyn激酶，然后诱导ERK1 / 2激活。全基因组微阵列分析表明，双稳态磷酸化ERK1 / 2（pERK1 / 2）不会诱导高水平的基因转录。这是由于它的核排斥和对Rab5 + 内体的分隔。具有持续的内体pERK1 / 2的细胞表现出对生长因子戒断诱导的细胞死亡的抵抗力。他们为增加细胞因子生产准备。人类哮喘病例和慢性哮喘小鼠模型的上皮细胞表现出pERK1 / 2升高，这与Rab5 + 内体有关。 pERK1 / 2的增加与这些组织中Sprouty 2表达的同时增加有关。因此，我们开发了一种持续ERK1 / 2激活的细胞模型，该模型可以提供对慢性疾病（例如哮喘）中自我维持的生物过程的机械理解。

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