TI - Suppression of glycogen synthase kinase activity is not sufficient for leukemia enhancer factor -1 activation . AB - 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 beta-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 beta-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 .