Disruption of Transforming Growth Factor-β Signaling in ELF β-Spectrin-Deficient Mice

Abstract

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. ELF deficiency results in mislocalization of Smad3 and Smad4 and loss of the TGF-beta-dependent transcriptional response, which could be rescued by overexpression of the COOH-terminal region of ELF. This study reveals an unexpected molecular link between a major dynamic scaffolding protein and a key signaling pathway.

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

“…The presence of mutations was monitored by use of the PCR as described previously (Tang et al, 2003). Out of 40 elf þ /À mice, 16 (40%) developed HCC, ranging from well to poorly differentiated carcinoma, as early as 15 months of age; however, none of the wild-type mice developed HCC (Figure 1a and b).…”

“…Antiproliferative responses of TGF-b occur primarily by inhibition of G 1 -S phase transition through activation of pRb, Cdk inhibitors, p15 and p21, as well as inhibition of c-Myc, Cdk2, Cdk4, cyclin E, cyclin A and cyclin D1 (Sherr, 1996;Siegel et al, 2003;Mishra et al, 2005;Knudsen et al, 2006). Smad function is highly dependent upon adaptor proteins such as embryonic liver fodrin (ELF), SARA and microtubules (Tsukazaki et al, 1998;Tang et al, 2003;Mishra et al, 2005). ELF, a b-spectrin, is first isolated from mouse E11 libraries and is shown to play a crucial role in the propagation of TGF-b signaling (Mishra et al, 1999).…”

“…Specifically, ELF associates with Smad3 and the TGF-b receptor complex; this interaction is followed by interaction with Smad4 and leads to their translocation to the nucleus. Disruption of elf expression by gene knockout was found to result in miscolocalization of Smad3 and Smad4, and disruption of TGF-b signaling (Tang et al, 2003). The epistatic significance of spontaneous and frequent HCC development in elf þ /À mutant mice presents an ideal model for further analysis of the role of ELF and TGF-b signaling in hepatocarcinogenesis.…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…For instance, TBRII is mutated in up to 30% of colon cancers,56 TBRI is mutated in 15% of biliary cancers,57, 58, 59 and SMAD4 is deleted in 40%‐60% of pancreatic cancers and mutated in gastrointestinal cancer 60. Loss of β2SP is observed in human HCC 14, 61, 62, 63. Evidence from Smad4‐knockout mice, which develop head and neck cancers, demonstrates a significant role for Smad4 in promoting genomic stability 64.…”

Non-erythroid beta spectrin interacting proteins and their effects on spectrin tetramerization

“…Furthermore, βI spectrin is absent from Purkinje cell dendrites [16]. βII participates in the propagation of TGF-β signaling [17]. Gene knock-out studies show that spectrin expression and regulation are important for fundamental cellular functions.…”