Sumoylation is involved in β‐catenin‐dependent activation of Tcf‐4

Sumoylation is involved in mediating protein–protein interactions, subcellular compartmentalization and protein stability. Our analysis of various Wnt signaling molecules revealed that one of them, Tcf‐4, is sumoylated at the endogenous level. At least one sumoylation site, Lys297, of Tcf‐4 was identified. The sumoylation of Tcf‐4 was enhanced by PIASy, a SUMO E3 enzyme, and inhibited by Axam, a desumoylation enzyme. Although PIASy did not affect the interaction of Tcf‐4 with β‐catenin or DNA, Tcf‐4, SUMO‐1 and PIASy were co‐localized in the nucleus and present in a complex in the PML body. PIASy enhanced β‐catenin‐dependent transcriptional activity of Tcf‐4, whereas Axam inhibited it. Reduction of the protein level of Axam by RNA interference led to an increase in sumoylation of Tcf‐4 and activation of Tcf‐4. Furthermore, β‐catenin and PIASy activated Tcf‐4K297R, in which Lys297 was changed to arginine, less than wild‐type Tcf‐4. These results suggest that sumoylation of Tcf‐4 is involved in β‐catenin‐dependent and Tcf‐4‐mediated gene expression in the Wnt signaling pathway.

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