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Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14110-5. Epub 2006 Sep 12.

beta-Arrestin2 mediates nephrin endocytosis and impairs slit diaphragm integrity.

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  • 1Department of Nephrology, Marienhospital Herne, Hospital of the University of Bochum, D-44625 Herne, Germany.

Abstract

beta-Arrestins mediate internalization of plasma membrane receptors. Nephrin, a structural component of the glomerular slit diaphragm, is a single transmembrane spanning receptor and belongs to the family of adhesion molecules. Its mutation causes a hereditary nephrotic syndrome. We report the previously undescribed interaction of beta-arrestin2 with the nephrin C terminus. The phosphorylation status of nephrin Y1193 regulates inversely the binding of beta-arrestin2 and podocin. The Src-family member Yes, known to enhance podocin-nephrin interaction by nephrin phosphorylation, diminishes beta-arrestin2-nephrin interaction. beta-Arrestin2 induces nephrin endocytosis and attenuates nephrin signaling. This finding suggests that nephrin Y1193 serves as a molecular switch that determines the integrity of the slit diaphragm by functional competition between beta-arrestin2 and podocin. This concept offers a molecular pathomechanism of slit diaphragm distortion and opens therapeutic avenues for glomerular diseases.

PMID:
16968782
[PubMed - indexed for MEDLINE]
PMCID:
PMC1564064
Free PMC Article
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