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J. Biol. Chem., Vol. 279, Issue 43, 44582-44589, October 22, 2004

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Differential Sensitivity of v-Myb and c-Myb to Wnt-1-induced Protein Degradation^*

Chie Kanei-Ishii, Teruaki Nomura, Jun Tanikawa, Emi Ichikawa-Iwata, and Shunsuke Ishii

From the Laboratory 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--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.

Received for publication, July 12, 2004 , and in revised form, August 10, 2004.

^* This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-29-836-9031; Fax: 81-29-836-9030; E-mail: sishii{at}rtc.riken.jp.

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				T. Kurahashi, T. Nomura, C. Kanei-Ishii, Y. Shinkai, and S. Ishii The Wnt-NLK Signaling Pathway Inhibits A-Myb Activity by Inhibiting the Association with Coactivator CBP and Methylating Histone H3 Mol. Biol. Cell, October 1, 2005; 16(10): 4705 - 4713. [Abstract] [Full Text] [PDF]