Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 36, Pages 13433-13438Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806298105
Keywords
AO7/RNF25; E3 ligase; Wnt antagonist
Categories
Funding
- National Cancer Institute/ National Institutes of Health [CA 46413]
- Special Program of Research Excellence [CA 95103]
- Mouse Models of Human Cancers Consortium [U01 084239]
- Vascular Biology Training [HL007751]
- Center for Cancer Research
- National Cancer Institute/National Institutes of Health
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Naked family members (Drosophila Naked Cuticle and mammalian Naked1 and Naked2) have been identified as inducible antagonists of canonical Wnt signaling. We recently reported that Naked2, but not Naked1, interacts with the cytoplasmic tail of TGF-alpha, thereby coating TGF-alpha-containing exocytic vesicles and directing these vesicles to the basolateral corner of polarized epithelial cells. Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2. These results identify an EGFR-independent action of TGF-alpha, in which it protects Naked2 from proteasomal degradation, thus ensuring its delivery to the basolateral surface of polarized epithelial cells.
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