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Division of Molecular Medicine and Genetics,
1
Departments of Internal Medicine,
2 Human Genetics, and
3 Pathology, University of Michigan Medical Center, Ann Arbor,
Michigan 48109-0638 USA;
4 Departments of Pharmacology and
5 Genetics, Yale University School of Medicine, New Haven,
Connecticut 06536-0812 USA;
6 Massachusetts General Hospital
Cancer Center, Charlestown, Massachusetts 02129 USA
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.
[Key Words: DCC; mammalian homologs; Drosophila sina gene; ubiquitin-proteasome pathway]
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