β-Catenin Phosphorylated at Serine 45 Is Spatially Uncoupled from β-Catenin Phosphorylated in the GSK3 Domain: Implications for Signaling

Abstract

C. elegans and Drosophila generate distinct signaling and adhesive forms of β-catenin at the level of gene expression. Whether vertebrates, which rely on a single β-catenin gene, generate unique adhesive and signaling forms at the level of protein modification remains unresolved. We show that β-catenin unphosphorylated at serine 37 (S37) and threonine 41 (T41), commonly referred to as transcriptionally Active β-Catenin (ABC), is a minor nuclear-enriched monomeric form of β-catenin in SW480 cells, which express low levels of E-cadherin. Despite earlier indications, the superior signaling activity of ABC is not due to reduced cadherin binding, as ABC is readily incorporated into cadherin contacts in E-cadherin-restored cells. β-catenin phosphorylated at serine 45 (S45) or threonine 41 (T41) (T41/S45) or along the GSK3 regulatory cassette S33, S37 or T41 (S33/37/T41), however, is largely unable to associate with cadherins. β-catenin phosphorylated at T41/S45 and unphosphorylated at S37 and T41 is predominantly nuclear, while β-catenin phosphorylated at S33/37/T41 is mostly cytoplasmic, suggesting that β-catenin hypophosphorylated at S37 and T41 may be more active in transcription due to its enhanced nuclear accumulation. Evidence that phosphorylation at T41/S45 can be spatially separated from phosphorylations at S33/37/T41 suggests that these phosphorylations may not always be coupled, raising the possibility that phosphorylation at S45 serves a distinct nuclear function.

Dickkopfs and Wnt/β-catenin signalling in liver cancer

“…The phosphorylated β-catenin is then ubiquitinated by β-transducin repeatcontaining protein (β-TrCP) and subsequently degraded by the proteasome [30] ( Figure 1A). Maher et al [31] reported that β-catenin phosphorylated at Ser45 and not at Ser33/ Ser37/Thr41 is predominantly located in the nucleus, whereas β-catenin phosphorylated at Ser33/Ser37/Thr41 is mostly localized to the cytoplasm. This spatial separation of β-catenin suggests that phosphorylation at Ser45 and at Ser33/Ser37/Thr41 is not necessarily coupled.…”

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

“…That being said however, the low levels of active -catenin were almost exclusively located in the nucleus. Furthermore, Maher et al, (2010) observed that -catenin phosphorylated at Thr41/Ser45 was spatially uncoupled from -catenin phosphorylated at Ser33/Ser37/Thr41. This suggested that phosphorylation at Ser45 by CK1 extended beyond a simple priming gesture (Maher et al, 2010).…”

“…Furthermore, Maher et al, (2010) observed that -catenin phosphorylated at Thr41/Ser45 was spatially uncoupled from -catenin phosphorylated at Ser33/Ser37/Thr41. This suggested that phosphorylation at Ser45 by CK1 extended beyond a simple priming gesture (Maher et al, 2010). Since the majority of the Thr41/Ser45 phosphorylated -catenin translocated to the nucleus, it is entirely possible that phosphorylation at Ser45 configures an active form of -catenin (Maher et al, 2010).…”

“…In addition to the subsequent recognition by -TrCP followed by proteosomal degradation, GSK3 and CK1 mediated phosphorylation has a major impact on the functionality of -catenin. Unmodified -catenin at GSK residues Ser33, Ser37 and Thr41 has been characterized as intrinsically more active than the pool ofcatenin that are phosphorylated (Staal et al, 2002;Maher et al, 2010). In other words, transactivation by -catenin can be altered by phosphorylation.…”

“…In other words, transactivation by -catenin can be altered by phosphorylation. Using monoclonal antibodies detecting for -catenin specifically unmodified at Ser37 and Thr41 (activecatenin), Maher et al, (2010) indicated that active -catenin exists in a monomeric form and was found in far fewer proportions relative to the total pool of -catenin. That being said however, the low levels of active -catenin were almost exclusively located in the nucleus.…”