Tcf-1-mediated transcription in T lymphocytes: differential role for glycogen synthase kinase-3 in fibroblasts and T cells

β-Catenin is the vertebrate homolog of the Drosophila segment polarity gene Armadillo and plays roles in both cell–cell adhesion and transduction of the Wnt signaling cascade. Recently, members of the Lef/Tcf transcription factor family have been identified as protein partners of β-catenin, explaining how β-catenin alters gene expression. Here we report that in T cells, Tcf-1 also becomes transcriptionally active through interaction with β-catenin, suggesting that the Wnt signal transduction pathway is operational in T lymphocytes as well. However, although Wnt signals are known to inhibit the activity of the negative regulatory protein kinase glycogen synthase kinase-3β (GSK-3β), resulting in increased levels of β-catenin, we find no evidence for involvement of GSK-3β in Tcf-mediated transcription in T cells. That is, a dominant negative GSK-3β does not specifically activate Tcf transcription and stimuli (lithium or phytohemagglutinin) that inhibit GSK-3β activity also do not activate Tcf reporter genes. Thus, inhibition of GSK-3β is insufficient to activate Tcf-dependent transcription in T lymphocytes. In contrast, in C57MG fibroblast cells, lithium inactivates GSK-3β and induces Tcf-controlled transcription. This is the first demonstration that lithium can alter gene expression of Tcf-responsive genes, and points to a difference in regulation of Wnt signaling between fibroblasts and lymphocytes.