Axin promotes the phosphorylation of beta-catenin by GSK-3beta, leading to beta-catenin degradation. Wnt signals interfere with beta-catenin turnover, resulting in enhanced transcription of target genes through the increased formation of beta-catenin complexes containing TCF transcription factors. Little is known about how GSK-3beta-mediated beta-catenin turnover is regulated in response to Wnt signals. We have explored the relationship between Axin and Dvl-2, a member of the Dishevelled family of proteins that function upstream of GSK-3beta. Expression of Dvl-2 activated TCF-dependent transcription. This was blocked by co-expression of GSK-3beta or Axin. Expression of a 59 amino acid GSK-3beta-binding region from Axin strongly activated transcription in the absence of an upstream signal. Introduction of a point mutation into full-length Axin that prevented GSK-3beta binding also generated a transcriptional activator. When co-expressed, Axin and Dvl-2 co-localized within expressing cells. When Dvl-2 localization was altered using a C-terminal CAAX motif, Axin was also redistributed, suggesting a close association between the two proteins, a conclusion supported by co-immunoprecipitation data. Deletion analysis suggested that Dvl-association determinants within Axin were contained between residues 603 and 810. The association of Axin with Dvl-2 may be important in the transmission of Wnt signals from Dvl-2 to GSK-3beta.

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The brk gene encodes a non-receptor tyrosine kinase that has been found to be overexpressed in approximately two thirds of breast tumours. Using a yeast two-hybrid based screen, we have cloned cDNAs encoding a novel protein, BKS, that is a substrate for the kinase activity of BRK and has the characteristics of an adaptor protein. BKS possesses an N-terminal PH-like domain followed by an SH2-like domain. In co-transfection experiments, high levels of phosphotyrosine were observed on BKS and BRK was found to be associated with BKS, both of which were dependent on the catalytic activity of BRK. The phosphorylation of and association with BKS by BRK was also dependent on the SH2-like domain present within BKS. In addition, BKS recruited an unidenti®ed 100 kDa protein that was also phosphorylated on tyrosine residues in the presence of BRK. We have determined that the BKS protein is expressed in most adult human tissues. Oncogene (2000) 19, 4273 ± 4282.

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