Syk-mediated tyrosine phosphorylation of mule promotes TNF-induced JNK activation and cell death.
Syk-mediated tyrosine phosphorylation of mule promotes TNF-induced JNK activation and cell death.
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作者：
Lee CK;Yang Y;Chen C;Liu J
转录因子Miz 1通过抑制TRAF 2 K63-多聚泛素化负调控TNF诱导的JNK活化和细胞死亡;在TNF刺激后，Mule/ARF-BP 1介导的Miz 1泛素化和随后的降解缓解了抑制。目前还不清楚Mule是如何被TNF激活的。在这里，我们报告说，TNF激活骡子诱导解离的骡子从其抑制剂ARF。ARF结合并从而抑制稳态下Mule的E3连接酶活性。TNF诱导Mule的酪氨酸磷酸化，其随后从ARF中解离并被激活。通过沉默脾酪氨酸激酶（Syk）抑制Mule磷酸化可防止其从ARF中解离，从而抑制Mule E3连接酶活性和TNF诱导的JNK活化和细胞死亡。我们的数据提供了导致JNK激活和细胞死亡的TNF信号通路中缺失的一环。
The transcription factor Miz1 negatively regulates TNF-induced JNK activation and cell death by suppressing TRAF2 K63-polyubiquitination; upon TNF stimulation, the suppression is relieved by Mule/ARF-BP1-mediated Miz1 ubiquitination and subsequent degradation. It is not known how Mule is activated by TNF. Here we report that TNF activates Mule by inducing the dissociation of Mule from its inhibitor ARF. ARF binds to and thereby inhibits the E3 ligase activity of Mule in the steady state. TNF induces tyrosine phosphorylation of Mule, which subsequently dissociates from ARF and becomes activated. Inhibition of Mule phosphorylation by silencing of the Spleen Tyrosine Kinase (Syk) prevents its dissociation from ARF, thereby inhibiting Mule E3 ligase activity and TNF-induced JNK activation and cell death. Our data provides a missing link in TNF signaling pathway that leads to JNK activation and cell death.