Colorectal Cancer-Associated Smad4 R361 Hotspot Mutations Boost Wnt/β-Catenin Signaling through Enhanced Smad4-LEF1 Binding.

ABSTRACT: About 10% to 30% of patients with colorectal cancer harbor either loss of or missense mutations in SMAD4, a critical component of the TGFβ signaling pathway. The pathophysiologic function of missense mutations in Smad4 is not fully understood. They usually map to the MH2 domain, specifically to residues that are involved in heterodimeric complex formation with regulatory Smads (such as Smad2/3) and ensuing transcriptional activation. These detrimental effects suggest that SMAD4 missense mutations can be categorized as loss-of-function. However, they tend to cluster in a few hotspots, which is more consistent with them acting by a gain-of-function mechanism. In this study, we investigated the functional role of Smad4 R361 mutants by re-expressing two R361 Smad4 variants in several Smad4-nul

SUBMITTER: Lanauze CB 

PROVIDER: S-EPMC8137583 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature