SCFβ-TrCP1 controls Smad4 protein stability in pancreatic cancer cells

Citations of this article
Mendeley users who have this article in their library.


Smad4, also known as deleted in pancreatic carcinoma locus 4 (DPC4), is a critical co-factor in signal transduction pathways activated by transforming growth factor (TGF)-β-related ligands that regulate cell growth and differentiation. Mutations in Smad4/ DPC4 have been identified in ∼50% of pancreatic adenocarcinomas. Here we report that SCFβ-TrCP1, a ubiquitin (E3) ligase, is a critical determinant for Smad4 protein degradation in pancreatic cancer cells. We found that F-box protein β-TrCP1 in this E3 ligase interacted with Smad4 and that SCFβ-TrCP1 inhibited TGF-β biological activity in pancreatic cancer cells by decreasing Smad4 stability. Very low Smad4 protein levels in human pancreatic ductal adenocarcinoma cells were observed by immunohistochemistry. By analyzing pancreatic tumor-derived Smad4 mutants, we found that most point-mutated Smad4 proteins, except those within or very close to a mutation cluster region, exhibited higher interaction affinity with β-TrCP1 and significantly elevated protein ubiquitination by SCFβ-TrCp1. Furthermore, AsPC-1 and Caco-2, two cancer cell lines harboring Smad4 point mutations, exhibited rapid Smad4 protein degradation due to the effect of SCF β-TrCp1. Both Smad4 levels and TGF-β signaling were elevated by retrovirus-delivered β-TrCP1 siRNA in pancreatic cancer cells. Therefore, inhibition of Smad4-specific E3 ligase might be a target for therapeutic intervention in pancreatic cancer.




Wan, M., Huang, J., Jhala, N. C., Tytler, E. M., Yang, L., Vickers, S. M., … Cao, X. (2005). SCFβ-TrCP1 controls Smad4 protein stability in pancreatic cancer cells. American Journal of Pathology, 166(5), 1379–1392.

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free