Wnt signaling through T-cell factor phosphorylation

Abstract

Embryonic signaling pathways often lead to a switch from default repression to transcriptional activation of target genes. A major consequence of Wnt signaling is stabilization of β-catenin, which associates with T-cell factors (TCFs) and 'converts' them from repressors into transcriptional activators. The molecular mechanisms responsible for this conversion remain poorly understood. Several studies have reported on the regulation of TCF by phosphorylation, yet its physiological significance has been unclear: in some cases it appears to promote target gene activation, in others Wnt-dependent transcription is inhibited. This review focuses on recent progress in the understanding of contextdependent post-translational regulation of TCF function by Wnt signaling.

Wnt Signaling in Vertebrate Axis Specification

“…Notably, Wnt8/HIPK2 signal can trigger the phosphorylation of TCF3, TCF4, and Lef1 (but not TCF1), owing to the conservation of the HIPK2 phosphorylation sites. Thus, context-dependent activation of early and late Wnt target genes may be explained by the opposing action of tissue-specific TCF proteins and their distinct response to Wnt8-mediated phosphorylation (Sokol 2011). Whether this explanation is correct remains to be experimentally tested.…”

“…The pathway leading to TCF regulation in vertebrates is reminiscent of Wnt signaling in C. elegans, because LIT-1, a homolog of Nlk, and WRM-1, a b-catenin paralog, phosphorylates POP-1/TCF to enhance its nuclear export, leading to transcriptional derepression (Rocheleau et al 1997(Rocheleau et al , 1999Meneghini et al 1999;Lo et al 2004). Because POP-1 plays a dual role in gene target regulation, the reader is referred to other reviews foradditional information (Phillips and Kimble 2009;Sokol 2011).…”

“…A critical event seems to be TCF3 phosphorylation by HIPK2 allowing one to derepress the target genes (Hikasa et al 2010;Sokol 2011), although in some cases TCF3 is likely to function in a Wnt-independent manner (Cole et al 2008;Gribble et al 2009). Homeodomain-interacting protein kinases (HIPKs) have been shown to function in a context-dependent manner in response to Wnt signaling (Wei et al 2007;Lee et al 2009;Louie et al 2009;Kim et al 2010).…”

“…Wnt proteins, such as Wnt1, Wnt3, and Wnt8, stimulate Frizzled and LRP5/6 receptors to inactivate this b-catenin destruction complex, and, at the same time, trigger the phosphorylation of TCF proteins by homeodomain-interacting protein kinase 2 (HIPK2) (Hikasa et al 2010;Hikasa and Sokol 2011). Both b-catenin stabilization and the regulation of TCF protein function by phosphorylation appear to represent general strategies that are conserved in multiple systems (Sokol 2011). Thus, the signaling pathway consists of two branches that together regulate target gene expression (Fig.…”

Prostate Cancer Progression to Androgen Independent Disease: The Role of the Wnt/β-Catenin Pathway

“…Although the exact sequence of events that occur once -catenin has translocated into the nucleus remains elusive, there are several models explaining the role of -catenin in gene activation. The simplest explains -catenin as a co-activator by providing a transcriptional activation domain to TCF/LEF (Sokol, 2011). Another model proposes thatcatenin heterodimerizes with TCF/LEF to supplant repressor proteins, Groucho/TLE, CtBP or HDACs, and thereby switching TCF/LEF from a quiescent state into one that is transcriptionally active (Stadeli et al, 2006;Sokol, 2011).…”