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J. Biol. Chem., Vol. 277, Issue 3, 2089-2096, January 18, 2002
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From the Bone morphogenetic proteins (BMPs) are expressed
broadly and regulate a diverse array of developmental events in
vivo. Essential to many of these functions is the establishment
of activity gradients of BMP, which provide positional information that
influences cell fates. Secreted polypeptides, such as Noggin, bind BMPs
and inhibit their function by preventing interaction with receptors on
the cell surface. These BMP antagonists are assumed to be diffusible and therefore potentially important in the establishment of BMP activity gradients in vivo. Nothing is known, however,
about the potential interactions between Noggin and components of the
cell surface or extracellular matrix that might limit its diffusion. We
have found that Noggin binds strongly to heparin in vitro, and to heparan sulfate proteoglycans on the surface of cultured cells.
Noggin is detected only on the surface of cells that express heparan
sulfate, can be specifically displaced from cells by heparin, and can
be directly cross-linked to a cell surface proteoglycan in culture.
Heparan sulfate-bound Noggin remains functional and can bind BMP4 at
the plasma membrane. A Noggin mutant with a deletion in a putative
heparin binding domain has reduced binding to heparin and does not bind
to the cell surface but has preserved BMP binding and antagonist
functions. Our results imply that interactions between Noggin and
heparan sulfate proteoglycans in vivo regulate diffusion
and therefore the formation of gradients of BMP activity.
Heparan Sulfate Proteoglycans Retain Noggin at the Cell
Surface
A POTENTIAL MECHANISM FOR SHAPING BONE MORPHOGENETIC PROTEIN
GRADIENTS*
,,¶
Department of Pediatrics, Washington
University School of Medicine and St. Louis Children's Hospital,
St. Louis, Missouri 63110, § Regeneron Pharmaceutical, Inc.,
Tarrytown, New York 10591, ¶ Department of Molecular Biology
and Pharmacology, Washington University School of Medicine,
St. Louis, Missouri 63110
*
These studies were supported in part by National Institutes
of Health Grant DK56063 (to S. S.) and March of Dimes Birth Defects Foundation Grant 6-FY99-441 (to S. S.).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.
Scholar of the Child Health Research Center of Excellence in
Developmental Biology at Washington University School of Medicine (Grant HD33688). To whom correspondence should be addressed: Washington University School of Medicine, Dept. of Pediatrics, 660 S. Euclid Ave.,
Campus Box 8208, St. Louis, MO 63110. Tel.: 314-286-2850; Fax:
314-286-2893; E-mail: saunders_s@kids.wustl.edu.
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