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Heparan Sulfate Proteoglycans Retain Noggin at the Cell
A POTENTIAL MECHANISM FOR SHAPING BONE MORPHOGENETIC PROTEIN
From the 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
Bone morphogenetic proteins (BMPs) are expressed
broadly and regulate a diverse array of developmental events in
vivo. Essentialto many of these functions is the establishment
of activity gradientsof BMP, which provide positional information that
influences cellfates. Secreted polypeptides, such as Noggin, bind BMPs
and inhibittheir function by preventing interaction with receptors on
thecell surface. These BMP antagonists are assumed to be diffusibleand therefore potentially important in the establishment of BMPactivity gradients in vivo. Nothing is known, however,
about thepotential interactions between Noggin and components of the
cellsurface 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 culturedcells.
Noggin is detected only on the surface of cells that expressheparan
sulfate, can be specifically displaced from cells by heparin,and can
be directly cross-linked to a cell surface proteoglycanin culture.
Heparan sulfate-bound Noggin remains functional andcan bind BMP4 at
the plasma membrane. A Noggin mutant with a deletionin a putative
heparin binding domain has reduced binding to heparinand does not bind
to the cell surface but has preserved BMP bindingand antagonist
functions. Our results imply that interactionsbetween Noggin and
heparan sulfate proteoglycans in vivo regulatediffusion
and therefore the formation of gradients of BMPactivity.