Suppression of Glycogen Synthase Kinase Activity Is Not Sufficient for Leukemia Enhancer Factor-1 Activation*
- From the Department of Pharmacology and Physiology, University of Rochester, New York 14642 and ‡Shanghai Institute of Biochemistry, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai, China
Abstract
Glycogen synthase kinase-3 (GSK) can be regulated by different signaling pathways including those mediated by protein kinase Akt and Wnt proteins. Wnt proteins are believed to activate a transcription factor leukemia enhancer factor-1 (LEF-1) by inhibiting GSK, and Akt was shown to phosphorylate GSK and inhibit its kinase activity. We investigated the effect of an activated Akt on the accumulation of cytosolic β-catenin and LEF-1-dependent transcription. Although the activated Akt, mAkt, clearly inhibited the kinase activity of GSK, mAkt alone did not induce accumulation of cytosolic β-catenin or activate LEF-1-dependent transcription. On the contrary, coexpressed Wnt-1 and Frat activated LEF-1 but did not show significant inhibition of GSK-mediated phosphorylation of a peptide substrate. However, mAkt could act synergistically with Wnt-1 or Frat to activate LEF-1. In addition, the interaction of GSK for Axin appeared to decrease in the presence of mAkt, whereas the interaction for Frat remained unchanged. Consistently, a GSK mutant with substitution of a Phe residue for residue Tyr-216, which showed one-fifth of kinase activity of the wild-type GSK, exhibited a reduced association for Axin than the wild-type GSK. These results suggest that inhibition of GSK kinase activity is not sufficient for activation of LEF-1 but may facilitate the activation by reducing the interaction of GSK for Axin. The additional mechanism for LEF-1 activation may require dissociation of GSK from Axin as Frat facilitates the dissociation of GSK from Axin.
Footnotes
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↵* This work was supported by Grants GM53162 and GM54167 from the National Institutes of Health (to D. W.) and from the National Heart Association, and from National Natural Science Foundation of China ( to L. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ To whom correspondence should be addressed. Tel.: 716-275-2029; Fax: 716-756-7757; E-mail: wud@pharmacol.rochester.edu.
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↵2 D. Kimelman, personal communication.
- Abbreviations:
- Zw3
-
Zeste-White 3
- GSK
-
glycogen synthase kinase
- APC
-
adenomatous polyposis coli
- Dsh/Dvl
-
dishevelled
- GFP
-
green fluorescence protein
- GBP
-
GSK-binding protein
- LacZ
-
β-galactosidase
- LEF-1
-
leukemia enhancer factor-1
- HA
-
hemagglutinin
- Wg
-
wingless
-
- Received April 1, 1999.
- Revision received July 21, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
