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J. Biol. Chem., Vol. 277, Issue 28, 25660-25667, July 12, 2002
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From the Department of Cell Biology, Medical University of South
Carolina, Charleston, South Carolina 29425-2204
Embryos deficient in the morphogen Sonic hedgehog
(Shh) or the endocytic receptor megalin exhibit common
neurodevelopmental abnormalities. Therefore, we have investigated the
possibility that a functional relationship exists between the two
proteins. During embryonic development, megalin was found to be
expressed along the apical surfaces of neuroepithelial cells and was
coexpressed with Shh in the ventral floor plate of the neural tube.
Using enzyme-linked immunosorbent assay, homologous ligand
displacement, and surface plasmon resonance techniques, it was found
that the amino-terminal fragment of Shh (N-Shh) bound to megalin with
high affinity. Megalin-expressing cells internalized N-Shh through a
mechanism that was inhibited by antagonists of megalin,
viz. anti-receptor-associated protein and anti-megalin
antibodies. Heparin also inhibited N-Shh endocytosis, implicating
proteoglycans in the internalization process, as has been described for
other megalin ligands. Use of chloroquine to inhibit lysosomal
proteinase activity showed that N-Shh endocytosed via megalin was not
efficiently targeted to the lysosomes for degradation. The ability of
megalin-internalized N-Shh to bypass lysosomes may relate to the
finding that the interaction between N-Shh and megalin was resistant to
dissociation with low pH. Together, these findings show that megalin is
an efficient endocytic receptor for N-Shh. Furthermore, they implicate
megalin as a new regulatory component of the Shh signaling pathway.
Megalin Functions as an Endocytic Sonic Hedgehog
Receptor*
,,
*
This work was supported by National Institutes of Health
Grant HL61873 and American Heart Association Grant 9950344N (to
W. S. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
§
To whom correspondence should be addressed: Dept. of Cell Biology,
Medical University of South Carolina, 171 Ashley Ave., Charleston, SC
29425-2204. Tel.: 843-792-5482; Fax: 843-792-0664; E-mail:
argraves@musc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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