BCL9-2 binds Arm/beta-catenin in a Tyr142-independent manner and requires Pygopus for its function in Wg/Wnt...

Area of Science:

• Developmental Biology
• Molecular Biology
• Cancer Research

Background:

• The Wingless (Wg)/Wnt signal transduction pathway regulates key developmental processes.
• Aberrant Wnt signaling is implicated in various cancers, including colorectal cancer.
• Legless (Lgs)/BCL9 and Pygopus are key components of the Wnt pathway, mediating beta-catenin transcriptional activity.

Purpose of the Study:

• To investigate the role of Tyrosine-142 phosphorylation of beta-catenin in Wnt signaling.
• To determine if BCL9-2, a homolog of Lgs, mediates Wnt signaling independently of Pygopus and beta-catenin phosphorylation.
• To compare the functional redundancy between BCL9 and BCL9-2 in Wg/Wnt signaling.

Main Methods:

• Utilized cell-based assays in cultured mammalian cells to assess beta-catenin transcriptional activity.
• Employed in vivo studies in Drosophila melanogaster to evaluate Wg signaling.
• Performed biochemical assays to analyze protein-protein interactions and phosphorylation events.

Main Results:

• Tyrosine-142 phosphorylation of beta-catenin is not critical for BCL9-2 recruitment or transcriptional activity in mammalian cells.
• This phosphorylation event is also dispensable for Wg signaling in Drosophila.
• BCL9-2 effectively rescues Lgs function in both cell culture and in vivo, contingent upon its interaction with Pygo.

Conclusions:

• BCL9-2 can functionally substitute for Lgs in Wnt signaling, highlighting a conserved mechanism.
• The interaction between BCL9-2 and Pygo is essential for its rescue activity.
• BCL9 and BCL9-2 appear to be largely redundant evolutionary duplicates of Legless, with distinct expression patterns but similar functions in Wnt signaling.