Cell-surface heparan sulfate proteoglycans potentiate chordin antagonism of bone morphogenetic protein signaling and are necessary for cellular uptake of chordin
Signaling by bone morphogenetic proteins (BMPs) plays a central role in early embryonic patterning, organogenesis, and homeostasis in a broad range of species. Chordin, an extracellular antagonist of BMP signaling, is thought to readily diffuse in tissues, thus forming gradients of BMP inhibition that result in reciprocal gradients of BMP signaling. The latter determine cell fates along the embryonic dorsoventral axis. The secreted protein Twisted Gastrulation (TSG) is thought to help shape BMP signaling gradients by acting as a cofactor that enhances Chordin inhibition of BMP signaling. Here, we demonstrate that mammalian Chordin binds heparin with an affinity similar to that of factors known to functionally interact with heparan sulfate proteoglycans (HSPGs) in tissues. We further demonstrate that Chordin binding in mouse embryonic tissues was dependent upon its interaction with cell-surface HSPGs and that Chordin bound to cell-surface HSPGs (e.g. syndecans), but not to basement membranes containing the HSPG perlecan. Surprisingly, mammalian TSG did not bind heparin unless prebound to Chordin and/or BMP-4, although Drosophila TSG has been reported to bind heparin on its own. Results are also presented that indicate that Chordin-HSPG interactions strongly potentiate the antagonism of BMP signaling by Chordin and are necessary for the retention and uptake of Chordin by cells. These data and others regarding Chordin diffusion have implications for the paradigm of how Chordin is thought to regulate BMP signaling in the extracellular space and how gradients of BMP signaling are formed.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2004 |
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| Erschienen: |
2004 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:279 |
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| Enthalten in: |
The Journal of biological chemistry - 279(2004), 49 vom: 03. Dez., Seite 51289-97 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jasuja, Reema [VerfasserIn] |
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| Anmerkungen: |
Date Completed 11.01.2005 Date Revised 06.02.2021 published: Print-Electronic Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM150559631 |
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| 100 | 1 | |a Jasuja, Reema |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Cell-surface heparan sulfate proteoglycans potentiate chordin antagonism of bone morphogenetic protein signaling and are necessary for cellular uptake of chordin |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Signaling by bone morphogenetic proteins (BMPs) plays a central role in early embryonic patterning, organogenesis, and homeostasis in a broad range of species. Chordin, an extracellular antagonist of BMP signaling, is thought to readily diffuse in tissues, thus forming gradients of BMP inhibition that result in reciprocal gradients of BMP signaling. The latter determine cell fates along the embryonic dorsoventral axis. The secreted protein Twisted Gastrulation (TSG) is thought to help shape BMP signaling gradients by acting as a cofactor that enhances Chordin inhibition of BMP signaling. Here, we demonstrate that mammalian Chordin binds heparin with an affinity similar to that of factors known to functionally interact with heparan sulfate proteoglycans (HSPGs) in tissues. We further demonstrate that Chordin binding in mouse embryonic tissues was dependent upon its interaction with cell-surface HSPGs and that Chordin bound to cell-surface HSPGs (e.g. syndecans), but not to basement membranes containing the HSPG perlecan. Surprisingly, mammalian TSG did not bind heparin unless prebound to Chordin and/or BMP-4, although Drosophila TSG has been reported to bind heparin on its own. Results are also presented that indicate that Chordin-HSPG interactions strongly potentiate the antagonism of BMP signaling by Chordin and are necessary for the retention and uptake of Chordin by cells. These data and others regarding Chordin diffusion have implications for the paradigm of how Chordin is thought to regulate BMP signaling in the extracellular space and how gradients of BMP signaling are formed | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a Bmp4 protein, mouse |2 NLM | |
| 650 | 7 | |a Bone Morphogenetic Protein 4 |2 NLM | |
| 650 | 7 | |a Bone Morphogenetic Proteins |2 NLM | |
| 650 | 7 | |a Epitopes |2 NLM | |
| 650 | 7 | |a Glycoproteins |2 NLM | |
| 650 | 7 | |a Heparan Sulfate Proteoglycans |2 NLM | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Heparin |2 NLM | |
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| 700 | 1 | |a Allen, Benjamin L |e verfasserin |4 aut | |
| 700 | 1 | |a Pappano, William N |e verfasserin |4 aut | |
| 700 | 1 | |a Rapraeger, Alan C |e verfasserin |4 aut | |
| 700 | 1 | |a Greenspan, Daniel S |e verfasserin |4 aut | |
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