PDF(Pubmed)
Abstract：
Thyroid hormones (THs) are essential in neuronal and glial cell development and differentiation, synaptogenesis, and myelin sheath formation. In addition to nuclear receptors, TH acts through αvβ3-integrin on the plasma membrane, influencing transcriptional regulation of signaling proteins that, in turn, affect adhesion and survival of nerve cells in various neurologic disorders. TH exhibits protective properties during brain hypoxia; however, precise intracellular mechanisms responsible for the preventive effects of TH remain unclear. In this study, we investigated the impact of TH on integrin αvβ3-dependent downstream systems in normoxic and hypoxic conditions of pheochromocytoma PC12 cells. Our findings reveal that triiodothyronine (T3), acting through αvβ3-integrin, induces activation of the JAK2/STAT5 pathway and suppression of the SHP2 in hypoxic PC12 cells. This activation correlates with the downregulation of the expression palmitoyltransferase-ZDHHC2 and ZDHHC9 genes, leading to a subsequent decrease in palmitoylation and phosphorylation of Fyn tyrosine kinase. We propose that these changes may occur due to STAT5-dependent epigenetic silencing of the palmitoyltransferase gene, which in turn reduces palmitoylation/phosphorylation of Fyn with a subsequent increase in the survival of cells. In summary, our study provides the first evidence demonstrating the involvement of integrin-dependent JAK/STAT pathway, SHP2 suppression, and altered post-translational modification of Fyn in protective effects of T3 during hypoxia.
摘要：
甲状腺激素（THs）在神经元和神经胶质细胞发育和分化中至关重要，突触发生,和髓鞘形成。除了核受体,TH通过αvβ3-整合素作用于质膜，影响信号蛋白的转录调节，反过来,在各种神经系统疾病中影响神经细胞的粘附和存活。TH在脑缺氧期间表现出保护特性；然而，负责TH预防作用的精确细胞内机制仍不清楚。在这项研究中,我们研究了TH对嗜铬细胞瘤PC12细胞常氧和低氧条件下整合素αvβ3依赖性下游系统的影响.我们的发现揭示了三碘甲状腺原氨酸(T3)，通过αvβ3-整合素起作用，在低氧PC12细胞中诱导JAK2/STAT5途径的激活和SHP2的抑制。这种激活与表达棕榈酰转移酶-ZDHHC2和ZDHHC9基因的下调相关，导致随后的棕榈酰化和Fyn酪氨酸激酶磷酸化降低。我们认为这些变化可能是由于STAT5依赖的棕榈酰转移酶基因的表观遗传沉默而发生的。这反过来减少了Fyn的棕榈酰化/磷酸化，随后增加了细胞的存活。总之,我们的研究提供了第一个证据，证明了整合素依赖性JAK/STAT通路的参与，SHP2抑制,Fyn的翻译后修饰改变了T3在缺氧过程中的保护作用。
