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Molecular and Cellular Biology, October 1999, p. 7147-7157, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Regulation of Glycogen Synthase Kinase 3beta and Downstream Wnt Signaling by Axin

Chester M. Hedgepeth,1 Matthew A. Deardorff,1 Kathleen Rankin,2,3 and Peter S. Klein1,2,3,*

Cell and Molecular Biology Graduate Group,1 Department of Medicine,2 and Howard Hughes Medical Institute,3 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148

Received 24 February 1999/Returned for modification 4 April 1999/Accepted 22 June 1999

Axin is a recently identified protein encoded by the fused locus in mice that is required for normal vertebrate axis formation. We have defined a 25-amino-acid sequence in axin that comprises the glycogen synthase kinase 3beta (GSK-3beta ) interaction domain (GID). In contrast to full-length axin, which has been shown to antagonize Wnt signaling, the GID inhibits GSK-3beta in vivo and activates Wnt signaling. Similarly, mutants of axin lacking key regulatory domains such as the RGS domain, which is required for interaction with the adenomatous polyposis coli protein, bind and inhibit GSK-3beta in vivo, suggesting that these domains are critical for proper regulation of GSK-3beta activity. We have identified a novel self-interaction domain in axin and have shown that formation of an axin regulatory complex in vivo is critical for axis formation and GSK-3beta activity. Based on these data, we propose that the axin complex may directly regulate GSK-3beta enzymatic activity in vivo. These observations also demonstrate that alternative inhibitors of GSK-3beta can mimic the effect of lithium in developing Xenopus embryos.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104-6148. Phone: (215) 898-2179. Fax: (215) 573-4320. E-mail: pklein{at}hhmi.upenn.edu.

Molecular and Cellular Biology, October 1999, p. 7147-7157, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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