Figure 2.

GSK3 regulation of STATs, Smads, β-catenin, and NFAT. Among the signal transducer and activator of transcription (STAT) family of transcription factors that are critical mediators of responses to cytokines and growth factors, GSK3 selectively promotes STAT3 and STAT5 activation [5,46,49]. Thus, regulation of transcription factors by GSK3 modulates both the expression of inflammatory molecules and cellular responses stimulated by cytokines. GSK3 also regulates Smad transcription factors that transduce signals generated by TGF-β and other stimulants of cell surface receptors to regulate gene expression [70-72]. The transcriptional co-activator β-catenin is phosphorylated by GSK3 in the Wnt signaling pathway, which targets β-catenin for proteosomal degradation. Inhibitors of GSK3 or activation of Wnt signaling induce stabilization of β-catenin that leads to its nuclear transport and accumulation to promote Tcf/LEF-mediated transcription. β-catenin also modulates activities of other transcription factors. For example, β-catenin negatively regulates bacteria-induced inflammation by inhibiting NF-κB [73], providing an indirect mechanism for GSK3 to promote NF-κB activity by down-regulating β-catenin. Increased β-catenin activity often contributes to the proliferation and survival of immune cells. β-catenin levels are low in unstimulated B cells, but B cell receptor activation triggers accumulation of β-catenin after inducing inhibition of GSK3 [74]. The T cell receptor (TCR) activates the NFATc (nuclear factor of activated T cells) family of transcription factors that promote antigenic and tolerogenic genetic programs. TCR signals induce nuclear localization of NFAT and GSK3 inactivates NFATc by phosphorylation-dependent stimulation of NFATc nuclear export [75]. Therefore, inhibition of GSK3 keeps NFATc active, mimicking the CD28 costimulatory signal for T cell proliferation [26,29,31]. Red arrows signify actions regulated by GSK3.