Notch interferes with the scaffold function of JNK-interacting protein 1 to inhibit the JNK signaling pathway
Notch interferes with the scaffold function of JNK-interacting protein 1 to inhibit the JNK signaling pathway
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DOI：
10.1073/pnas.0501600102
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发表时间：
2005-10-04
影响因子：
11.1
通讯作者：
Choi, EJ
中科院分区：
文献类型：
--
作者：
Kim, JW;Kim, MJ;Choi, EJ
跨膜蛋白Notch被伽马分泌酶切割，产生一个活性形式，Notch胞内域(Notch-IC)，以响应配体的结合，如锯齿状。Noch-IC参与调节多种细胞事件，包括胚胎发育过程中细胞命运的决定以及细胞的生长、分化和存活。我们现在发现Notch1-IC抑制了JNK信号通路中c-Jun氨基末端激酶(JNK)相互作用蛋白1(JIP1)的支架活性。NOTCH1-IC物理上与J1P1的JNK结合域结合，从而干扰J1P1与JNK之间的相互作用。JLP1介导了缺糖诱导的小鼠胚胎成纤维细胞JNK1的激活，而Notch1-IC的异位表达抑制了缺糖诱导的JNK激活和细胞凋亡。综上所述，这些发现表明Notch1-IC通过破坏JIP1的支架功能来负向调节JNK途径。
The transmembrane protein Notch is cleaved by gamma-secretase to yield an active form, Notch intracellular domain (Notch-IC), in response to the binding of ligands, such as Jagged. Notch-IC contributes to the regulation of a variety of cellular events, including cell fate determination during embryonic development as well as cell growth, differentiation, and survival. We now show that Notch1-IC suppresses the scaffold activity of c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1) in the JNK signaling pathway. Notch1-IC physically associated with the JNK binding domain of JlP1 and thereby interfered with the interaction between JlP1 and JNK. JlP1 mediated the activation of JNK1 induced by glucose deprivation in mouse embryonic fibroblasts, and ectopic expression of Notch1-IC inhibited JNK activation and apoptosis triggered by glucose deprivation. Taken together, these findings suggest that Notch1-IC negatively regulates the JNK pathway by disrupting the scaffold function of JIP1.