The role of PRAJA and ELF in TGF-beta signaling and gastric cancer.

Lopa Mishra, Varalakshmi Katuri, Stephen Evans

Research output: Contribution to journalArticle

Abstract

Emerging research has shown that the transforming growth factor-beta (TGF-beta) pathway plays a key role in the suppression of gastric carcinoma. Biological signals for TGF-beta are transduced through transmembrane serine/threonine kinase receptors, which in turn signal to Smad proteins. Inactivation of the TGF-beta pathway often occurs in malignancies of the gastrointestinal system, including gastric cancer. Yet, only a fraction of sporadic gastric tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Smad4, a tumor suppressor, is often mutated in human gastrointestinal cancers. The mechanism of Smad4 inactivation, however, remains uncertain and could be mediated through E3-mediated ubiquitination of Smad4/adaptor protein complexes. The regulation of the TGF-beta pathway through a PRAJA, a RING finger (RING-H2) protein, and ELF, a beta-Spectrin adaptor protein, both which were originally identified in endodermal stem/progenitor cells committed to foregut lineage, could play a pivotal role in gastric carcinogenesis. PRAJA, which functions as an E3 ligase, interacts with ELF in a TGF-beta-dependent manner in gastric cancer cell lines. PRAJA is increased five-fold in human gastric cancers, and inactivates ELF. This is particularly significant since ELF, a Smad4 adaptor protein, possesses potent anti-oncogenic activity and is frequently seen to be inactivated in carcinogenic gastric cells. Strikingly, PRAJA manifests substantial E3-dependent ubiquitination of ELF and Smad3, but not Smad4. The alteration of ELF and/or Smad4 expression and function in the TGF-beta signaling pathway may be induced by enhancement of ELF degradation, which is mediated by the high level expression of PRAJA in gastrointestinal cancers. These studies reveal a mechanism for gastric tumorigenesis whereby defects in adaptor proteins for Smads, such as ELF, can undergo degradation by PRAJA, through the ubiquitin-mediated pathway.

Original languageEnglish (US)
Pages (from-to)694-699
Number of pages6
JournalCancer Biology and Therapy
Volume4
Issue number7
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

Transforming Growth Factor beta
Stomach Neoplasms
Stomach
Smad4 Protein
Gastrointestinal Neoplasms
Ubiquitination
Neoplasms
Carcinogenesis
Stem Cells
Smad Proteins
Spectrin
Proteins
Ubiquitin-Protein Ligases
Protein-Serine-Threonine Kinases
Ubiquitin
Carcinoma
Cell Line
Mutation
Research

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mishra, L., Katuri, V., & Evans, S. (2005). The role of PRAJA and ELF in TGF-beta signaling and gastric cancer. Cancer Biology and Therapy, 4(7), 694-699.

The role of PRAJA and ELF in TGF-beta signaling and gastric cancer. / Mishra, Lopa; Katuri, Varalakshmi; Evans, Stephen.

In: Cancer Biology and Therapy, Vol. 4, No. 7, 07.2005, p. 694-699.

Research output: Contribution to journalArticle

Mishra, L, Katuri, V & Evans, S 2005, 'The role of PRAJA and ELF in TGF-beta signaling and gastric cancer.', Cancer Biology and Therapy, vol. 4, no. 7, pp. 694-699.
Mishra, Lopa ; Katuri, Varalakshmi ; Evans, Stephen. / The role of PRAJA and ELF in TGF-beta signaling and gastric cancer. In: Cancer Biology and Therapy. 2005 ; Vol. 4, No. 7. pp. 694-699.
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