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PMID: 9334332 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Genes & development ·Vol. 11 ·No. 20 ·1997-10-15 ·Pages 2701-14

Hu G, Zhang S, Vidal M, Baer JL, Xu T, Fearon ER

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.

MeSH Terms
Animals Animals, Genetically Modified CHO Cells COS Cells Cell Adhesion Molecules/biosynthesis,metabolism Cell Line Cricetinae DCC Receptor Drosophila Gene Library Genes, DCC Glioblastoma/genetics Humans Mammals Nuclear Proteins/biosynthesis,genetics Receptors, Cell Surface Recombinant Fusion Proteins/biosynthesis Saccharomyces cerevisiae Transfection Transplantation, Heterologous Tumor Cells, Cultured Tumor Suppressor Proteins Ubiquitin-Protein Ligases
Chemicals
Cell Adhesion Molecules DCC Receptor DCC protein, human Nuclear Proteins Receptors, Cell Surface Recombinant Fusion Proteins Tumor Suppressor Proteins Ubiquitin-Protein Ligases seven in absentia proteins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hu G
Division of Molecular Medicine and Genetics, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0638 USA.
Zhang S
Vidal M
Baer J L
Xu T
Fearon E R
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.11.20.2701
Published
1997-10-15
Pages
2701-14
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316613
Subset
IM
Grants
NCI NIH HHS · CA70097 · United States
External Links
PubMed source DOI: 10.1101/gad.11.20.2701 PMC Full Text View journal details
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