The endometrial cancer A230V-ALK5 (TGFBR1) mutant attenuates TGF-β signaling and exhibits reduced in vitro sensitivity to ALK5 inhibitors.

ABSTRACT: The ALK5 (TGFBR1) receptor serine/threonine kinase transduces TGF-β (Transforming Growth Factor beta) signaling to activate SMAD2/3-dependent and -independent pathways. Here, we aimed to determine the functional consequences of ALK5 mutations in human endometrial cancer (EC). Somatic mutation data were retrieved from publicly available databases. Using seven in silico algorithms, 78.5% (11 of 14) of ALK5 kinase domain mutations in EC, including A230V-ALK5, were predicted to impact protein function. For in vitro studies, we focused on A230V-ALK5 because it was the only mutated residue located within the ATP-binding pocket, which is an important region for both ATP-binding and binding of ATP-competitive inhibitors. Constructs expressing wildtype-, constitutively-active-, kinase-dead-, or mut

SUBMITTER: Yu EJ 

PROVIDER: S-EPMC11584080 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature