The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the association with coactivator CBP and methylating histone H3
The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the association with coactivator CBP and methylating histone H3
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DOI：
10.1091/mbc.e05-05-0470
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发表时间：
2005-10-01
影响因子：
3.3
通讯作者：
Ishii, S
中科院分区：
文献类型：
--
作者：
Kurahashi, T;Nomura, T;Ishii, S
C-myb原癌基因产物(c-Myb)调节造血细胞的增殖和分化。最近，我们发现c-Myb在WNT-1刺激下被降解，其途径涉及TAK1(转化生长因子-β激活的激酶)、HIPK2(同源结构域相互作用的蛋白激酶2)和NLK(Nemo-like Kinase)。NLK和HIPK2直接与c-Myb结合并在多个位点磷酸化c-Myb，导致其泛素化和蛋白酶体依赖的降解。哺乳动物MYB基因家族除c-MYB、A-MYB和B-MYB外，还有两个成员。在这里，我们报告了Wnt-NLK途径也抑制了A-Myb的活性，但机制不同。与c-Myb的情况一样，NLK和HIPK2都直接与A-Myb结合并抑制其活性。NLK可使A-Myb磷酸化，但不能诱导A-Myb降解。NLK的过表达抑制了A-Myb与辅活化子CBP的结合，从而阻断了A-Myb诱导的反式激活。NLK的激酶活性是有效抑制A-Myb和CBP之间结合所必需的，尽管NLK的激酶阴性形式也部分抑制了A-Myb和CBP之间的相互作用。此外，NLK还诱导组蛋白H3在A-Myb结合启动子区域的赖氨酸-9位发生甲基化。因此，Wnt-NLK途径通过不同的机制抑制Myb家族每个成员的活性。
The c-myb proto-oncogene product (c-Myb) regulates proliferation and differentiation of hematopoietic cells. Recently we have shown that c-Myb is degraded in response to Wnt-1 stimulation via a pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). NLK and HIPK2 bind directly to c-Myb and phosphorylate c-Myb at multiple sites, inducing its ubiquitination and proteasome-dependent degradation. The mammalian myb gene family contains two members in addition to c-myb, A-myb, and B-myb. Here, we report that the Wnt-NLK pathway also inhibits A-Myb activity, but by a different mechanism. As in the case of c-Myb, both NLK and HIPK2 bound directly to A-Myb and inhibited its activity. NLK phosphorylated A-Myb, but did not induce A-Myb degradation. Overexpression of NLK inhibited the association between A-Myb and the coactivator CBP, thus, blocking A-Myb-induced trans-activation. The kinase activity of NLK is required for the efficient inhibition of the association between A-Myb and CBP, although the kinase-negative form of NLK also partly inhibits the interaction between A-Myb and CBP. Furthermore, NLK induced the methylation of histone H3 at lysine-9 at A-Myb-bound promoter regions. Thus, the Wnt-NLK pathway inhibits the activity of each Myb family member by different mechanisms.