Differential sensitivity of v-Myb and c-Myb to Wnt-1-induced protein degradation
Differential sensitivity of v-Myb and c-Myb to Wnt-1-induced protein degradation
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DOI：
10.1074/jbc.m407831200
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发表时间：
2004-10-22
影响因子：
4.8
通讯作者：
Ishii, S
中科院分区：
文献类型：
--
作者：
Kanei-Ishii, C;Nomura, T;Ishii, S
最近我们发现，c-myb 原癌基因产物 (c-Myb) 通过涉及 TAK1（转化生长因子-β 激活激酶）、HIPK2（同源结构域相互作用蛋白激酶 2）和 NLK（Nemo 样激酶）的途径响应 Wnt-1 信号传导而被降解。 NLK 和 HIPK2 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。禽成髓细胞瘤病毒携带的v-myb基因具有转化能力，而c-myb原癌基因则没有。在这里，我们报告 v-Myb 的两个特性使其对 Wnt-1 诱导的蛋白质降解具有相对抵抗力。首先，HIPK2 与 v-Myb DNA 结合结构域的结合亲和力低于与 c-Myb 的结合亲和力。 v-Myb 中 DNA 结合结构域表面的三个疏水性氨基酸的突变降低了与 HIPK2 的亲和力。其次，c-Myb C 末端区域的截短导致多个 NLK 磷酸化位点的丢失，从而增加了其稳定性。在小鼠 c-Myb 的 15 个假定的 NLK 磷酸化位点中，C 末端区域的磷酸化位点比其他位点对于 Wnt-1 诱导的蛋白质降解更为关键。 v-Myb对Wnt-1诱导的降解的相对抗性可以至少部分地解释v-Myb相对于c-Myb的差异转化能力。
Recently we have shown that the c-myb proto-oncogene product (c-Myb) is degraded in response to Wnt-1 signaling via the pathway involving TAK1 ( transforming growth factor-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). NLK and HIPK2 bind directly to c-Myb, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. The v-myb gene carried by avian myeloblastosis virus has a transforming capacity, but the c- myb proto-oncogene does not. Here, we report that two characteristics of v-Myb make it relatively resistant to Wnt-1-induced protein degradation. First, HIPK2 binds with a lower affinity to the DNA-binding domain of v-Myb than to that of c-Myb. The mutations of three hydrophobic amino acids on the surface of the DNA-binding domain in v-Myb decrease the affinity to HIPK2. Second, a loss of multiple NLK phosphorylation sites by truncation of the C-terminal region of c- Myb increases its stability. Among 15 putative NLK phosphorylation sites in mouse c- Myb, the phosphorylation sites in the C-terminal region are more critical than other sites for Wnt-1-induced protein degradation. The relative resistance of v-Myb to Wnt-1-induced degradation may explain, at least in part, the differential transforming capacity of v-Myb versus c- Myb.