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J Biol Chem. 2004 Oct 22;279(43):44582-9. Epub 2004 Aug 11.

Differential sensitivity of v-Myb and c-Myb to Wnt-1-induced protein degradation.

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  • 1Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.


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.

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