Wnt signaling regulates cell fate determination, proliferation, and survival, among other processes. Certain Wnt ligands stabilize the beta-catenin protein, leading to the ability of beta-catenin to activate T cell factor-regulated genes. In the absence of Wnts, beta-catenin is phosphorylated at defined serine and threonine residues in its amino (N) terminus. The phosphorylated beta-catenin is recognized by a beta-transducin repeat-containing protein (betaTrCP) and associated ubiquitin ligase components. The serine/threonine residues and betaTrCP-binding site in the N-terminal region of beta-catenin constitute a key regulatory motif targeted by somatic mutations in human cancers, resulting in constitutive stabilization of the mutant beta-catenin proteins. Structural studies have implicated beta-catenin lysine 19 as the major target for betaTrCP-dependent ubiquitination, but Lys-19 mutations in cancer have not been reported. We studied the consequences of single amino acid substitutions of the only 2 lysine residues in the N-terminal 130 amino acids of beta-catenin. Mutation of Lys-19 minimally affected beta-catenin levels and functional activity, and mutation of Lys-49 led to reduced beta-catenin levels and function. In contrast, beta-catenin proteins with substitutions at both Lys-19 and Lys-49 positions were present at elevated levels and had the ability to potently activate T cell factor-dependent transcription and promote neoplastic transformation. We furthermore demonstrate that the K19/K49 double mutant forms of beta-catenin are stabilized as a result of reduced betaTrCP-dependent ubiquitination. Our findings suggest that Lys-19 is a primary in vivo site of betaTrCP-dependent ubiquitination and Lys-49 may be a secondary or cryptic site. Moreover, our results inform understanding of why single amino acid substitutions at lysine 19 or 49 have not been reported in human cancer.
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