Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK
Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK
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DOI：
10.1101/gad.1170604
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发表时间：
2004-04-01
影响因子：
10.5
通讯作者：
Ishii, S
中科院分区：
文献类型：
--
作者：
Kanei-Ishii, C;Ninomiya-Tsuji, J;Ishii, S
c-myb原癌基因产物（c-Myb）通过诱导一组靶基因的转录来调节造血细胞的增殖和凋亡。然而，调节c-Myb活性的生物学相关分子机制仍不清楚。在这里，我们报告，c-Myb蛋白磷酸化和降解Wnt-1信号通过途径涉及TAK 1（TGF-β激活激酶），HIPK 2（同源结构域相互作用蛋白激酶2），NLK（Nemo样激酶）。Wnt-1信号导致TAK 1进入细胞核，然后激活HIPK 2和丝裂原活化蛋白（MAP）激酶样激酶NLK。NLK与HIPK 2一起直接与c-Myb结合，导致c-Myb在多个位点磷酸化，随后发生泛素化和蛋白酶体依赖性降解。此外，NLK在M1细胞中的过表达消除了c-Myb维持这些细胞未分化状态的能力。Wnt-1信号对Myb的下调可能在多种发育过程中发挥重要作用。
The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps.