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

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.

Pubmed ID: 16714285


  • Yamada M
  • Ohnishi J
  • Ohkawara B
  • Iemura S
  • Satoh K
  • Hyodo-Miura J
  • Kawachi K
  • Natsume T
  • Shibuya H


The Journal of biological chemistry

Publication Data

July 28, 2006

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Humans
  • Molecular Sequence Data
  • Nuclear Proteins
  • Oocytes
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • TCF Transcription Factors
  • Two-Hybrid System Techniques
  • Ubiquitin
  • Xenopus
  • beta Catenin