The role of PRAJA and ELF in TGF-beta signaling and gastric cancer.
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.
Mishra
Lopa
L
Laboratory of GI Developmental Biology, Department of Surgery, Medicine and The Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA.lm229@georgetown.edu
Katuri
Varalakshmi
V
Evans
Stephen
S
D036383:Ephrin-A2 / Q000502:physiology*; D006801:Humans; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D036383:Ephrin-A2; D011506:Proteins; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C484661:PJA1 protein, human; D044767:Ubiquitin-Protein Ligases