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Lysine residues Lys-19 and Lys-49 of beta-catenin regulate its levels and function in T cell factor transcriptional activation and neoplastic transformation.

Winer IS, Bommer GT, Gonik N, Fearon ER
The Journal of biological chemistry


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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