2. Academic Validation
  3. NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF)

NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF)

  • J Biol Chem. 2006 Jul 28;281(30):20749-20760. doi: 10.1074/jbc.M602089200.
Misato Yamada 1,  Junji Ohnishi 1,  Bisei Ohkawara 1,  Shunichiro Iemura 2,  Kiyotoshi Satoh 1,  Junko Hyodo-Miura 3,  Kaoru Kawachi 1,  Tohru Natsume 2,  Hiroshi Shibuya 4
Affiliations

Affiliations

  • 1 Department of Molecular Cell Biology, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, and SORST, JST, Chiyoda-ku, Tokyo 101-0062.
  • 2 National Institutes of Advanced Industrial Science and Technology, Biological Information Research Center (JBIRC), Kohtoh-ku, Tokyo 135-0064.
  • 3 Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan.
  • 4 Department of Molecular Cell Biology, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, and SORST, JST, Chiyoda-ku, Tokyo 101-0062; Center of Excellence Program for Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Chiyoda, Tokyo 101-0062. Electronic address: shibuya.mcb@mri.tmd.ac.jp.
PMID: 16714285 DOI: 10.1074/jbc.M602089200
Abstract

beta-Catenin is a key player in the Wnt signaling pathway, and interacts with cofactor T cell factor/lymphoid enhancer factor (TCF/LEF) to generate a transcription activator complex that activates Wnt-induced genes. We previously reported that Nemo-like kinase (NLK) negatively regulates Wnt signaling via phosphorylation of TCF/LEF. To further evaluate the physiological roles of NLK, we performed yeast two-hybrid screening to identify NLK-interacting proteins. From this screen, we isolated a novel RING finger protein that we term NARF (NLK associated RING finger protein). Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating Enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the Proteasome. Furthermore, NARF inhibited formation of the secondary axis induced by the ectopic expression of beta-catenin in Xenopus embryos. Collectively, our findings raise the possibility that NARF functions as a novel ubiquitin-ligase to suppress the Wnt-beta-catenin signaling.

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