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  • The EMBO Journal (1999) 18, 4233 - 4240
  • doi:10.1093/emboj/18.15.4233

Axin and Frat1 interact with Dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1

Lin Li2,6, Huidong Yuan1,6, Carole D. Weaver3, Junhao Mao1, Gist H. Farr III3, Daniel J. Sussman4, Jos Jonkers5, David Kimelman3 and Dianqing Wu1

  1. Department of Pharmacology and Physiology, University of Rochester, NY 14642, USA
  2. Shanghai Institute of Biochemistry, The Chinese Academy of Sciences, Shanghai, Peoples Republic of China
  3. Department of Biochemistry, University of Washington, Seattle, WA 98195-7350, USA
  4. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, MD, USA
  5. Division of Molecular Genetics, The Netherlands Cancer Institute, Amersterdam, The Netherlands
  6. L.Li and H.Yuan contributed equally to this work

Correspondence to:

Dianqing Wu, E-mail: dianqing_wu@urmc.rochester.edu

Received 3 May 1999; Accepted 15 June 1999; Revised 15 June 1999

Wnt proteins transduce their signals through dishevelled (Dvl) proteins to inhibit glycogen synthase kinase 3beta (GSK), leading to the accumulation of cytosolic beta-catenin and activation of TCF/LEF-1 transcription factors. To understand the mechanism by which Dvl acts through GSK to regulate LEF-1, we investigated the roles of Axin and Frat1 in Wnt-mediated activation of LEF-1 in mammalian cells. We found that Dvl interacts with Axin and with Frat1, both of which interact with GSK. Similarly, the Frat1 homolog GBP binds Xenopus Dishevelled in an interaction that requires GSK. We also found that Dvl, Axin and GSK can form a ternary complex bridged by Axin, and that Frat1 can be recruited into this complex probably by Dvl. The observation that the Dvl-binding domain of either Frat1 or Axin was able to inhibit Wnt-1-induced LEF-1 activation suggests that the interactions between Dvl and Axin and between Dvl and Frat may be important for this signaling pathway. Furthermore, Wnt-1 appeared to promote the disintegration of the Frat1–Dvl–GSK–Axin complex, resulting in the dissociation of GSK from Axin. Thus, formation of the quaternary complex may be an important step in Wnt signaling, by which Dvl recruits Frat1, leading to Frat1-mediated dissociation of GSK from Axin.

  • Keywords:

    • Axin,
    • dishevelled,
    • Frat1,
    • GSK,
    • Wnt signalling