Mammalian homologs of seven in absentia regulate DCC via the ubiquitin- proteasome pathway

Gang Hu, Sheng Zhang, Marc Vidal, Joshua La Baer, Tian Xu, Eric R. Fearon

Research output: Contribution to journalArticle

173 Scopus citations

Abstract

DCC (deleted in colorectal cancer) is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1. We report here that the DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene, as well as Drosophila Sina. Sina has a critical role in R7 photoreceptor development and shows upward of 85% amino acid identity with its mammalian homologs (termed Siahs), but the function of the Sina/Siah proteins has not been defined. We sought, therefore, to characterize further their interaction with DCC. Immunofluorescence studies suggested the Sina/Siah proteins localized predominantly in the cytoplasm and in association with DCC. DCC was found to be ubiquitinated and the Sina/Siah proteins regulated its expression. Proteasome inhibitors blocked the effects of Sina/Siah on DCC, and the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs). A mutant Siah protein lacking the amino-terminal Ubc-binding sequences complexed with DCC, but did not degrade it. The in vivo interaction between Sina/Siah and DCC was confirmed through studies of transgenic Drosophila lines in which DCC and Sina were ectopically expressed in the eye. Taken together, the data imply that the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway.

Original languageEnglish (US)
Pages (from-to)2701-2714
Number of pages14
JournalGenes and Development
Volume11
Issue number20
DOIs
StatePublished - Oct 15 1997

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Keywords

  • DCC
  • Drosophila sina gene
  • Mammalian homologs
  • Ubiquitin-proteasome pathway

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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