Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK

被引:147
作者
Kanei-Ishii, C
Ninomiya-Tsuji, J
Tanikawa, J
Nomura, T
Ishitani, T
Kishida, S
Kokura, K
Kurahashi, T
Ichikawa-Iwata, E
Kim, Y
Matsumoto, K
Ishii, S [1 ]
机构
[1] RIKEN, Tsukuba Inst, Mol Genet Lab, Tsukuba, Ibaraki 3050074, Japan
[2] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan
[3] Nagoya Univ, Grad Sch Sci, Dept Mol Biol, Chikusa Ku, Nagoya, Aichi 4648602, Japan
[4] Japan Sci & Technol Corp, CREST, Chikusa Ku, Nagoya, Aichi 4648602, Japan
[5] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA
关键词
Myb; HIPK2; NLK; TAK1; phosphorylation; degradation;
D O I
10.1101/gad.1170604
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:816 / 829
页数:14
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