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Vol. 16, Issue 10, 4705-4713, October 2005

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The Wnt–NLK Signaling Pathway Inhibits A-Myb Activity by Inhibiting the Association with Coactivator CBP and Methylating Histone H3

Toshihiro Kurahashi ^* , Teruaki Nomura ^* , Chie Kanei-Ishii ^*, Yoichi Shinkai , and Shunsuke Ishii ^* 

^* Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, Tsukuba, Ibaraki 305-0074, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; and Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Sakyoku, Kyoto 606-8507, Japan

Submitted May 31, 2005; Revised July 13, 2005; Accepted July 18, 2005
Monitoring Editor: William Tansey

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--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.

Abbreviations used: A-Myb, A-myb gene product; ChIP, chromatin immunoprecipitation; c-Myb, c-myb proto-oncogene product; DBD, DNA-binding domain; H3K9, lysine-9 of histone H3; HIPK2, homeodomain-interacting protein kinase 2; HMTase, histone methyltransferase; NLK, Nemo-like kinase; NRD, negative regulatory domain; TAK1, TGF--activated kinase 1; TSA, trichostatin A.

Address correspondence to: Shunsuke Ishii (sishii{at}rtc.riken.jp).

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