Orofacial and gastrointestinal hyperplasia and neoplasia in smad4+/- and elf+/-/smad4+/- mutant mice.

Background: Smad4 is vital to the roles of Smads 2 and 3 in transforming growth factor-beta (TGF)-beta signal transduction, and inactivated Smad4 is common to human gastrointestinal cancers. The embryonic liver fodrin (ELF) is a beta-spectrin that facilitates the nuclear translocation of activated Smad4.

Methods: Smad4+/- mice, known to develop gastrointestinal cancer, were crossbred with elf+/- mice.

Disruption of transforming growth factor-beta signaling in ELF beta-spectrin-deficient mice.

Disruption of the adaptor protein ELF, a beta-spectrin, leads to disruption of transforming growth factor-beta (TGF-beta) signaling by Smad proteins in mice. Elf-/- mice exhibit a phenotype similar to smad2+/-/smad3+/- mutant mice of midgestational death due to gastrointestinal, liver, neural, and heart defects. We show that TGF-beta triggers phosphorylation and association of ELF with Smad3 and Smad4, followed by nuclear translocation.