Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7
Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during diabetic nephropa...
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| Veröffentlicht in: | Biochemical journal 2015-02, Vol.466 (1), p.55-68 |
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| creator | Church, Rachel H Krishnakumar, Arjun Urbanek, Annika Geschwindner, Stefan Meneely, Julie Bianchi, Alessandro Basta, Barbro Monaghan, Sean Elliot, Christopher Strömstedt, Maria Ferguson, Neil Martin, Finian Brazil, Derek P |
| description | Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during diabetic nephropathy (DN) has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. In the present study, we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK (human embryonic kidney)-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readouts, Grem1 consistently demonstrated a higher affinity for BMP-2>BMP-4>BMP-7. Cell-associated Grem1 did not inhibit BMP-2- or BMP-4-mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated. |
| doi_str_mv | 10.1042/BJ20140771 |
| format | Article |
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Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during diabetic nephropathy (DN) has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. In the present study, we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK (human embryonic kidney)-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readouts, Grem1 consistently demonstrated a higher affinity for BMP-2>BMP-4>BMP-7. Cell-associated Grem1 did not inhibit BMP-2- or BMP-4-mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. 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Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during diabetic nephropathy (DN) has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. In the present study, we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK (human embryonic kidney)-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readouts, Grem1 consistently demonstrated a higher affinity for BMP-2>BMP-4>BMP-7. Cell-associated Grem1 did not inhibit BMP-2- or BMP-4-mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.</description><subject>Bone Morphogenetic Protein 2 - genetics</subject><subject>Bone Morphogenetic Protein 2 - metabolism</subject><subject>Bone Morphogenetic Protein 4 - genetics</subject><subject>Bone Morphogenetic Protein 4 - metabolism</subject><subject>Bone Morphogenetic Protein 7 - genetics</subject><subject>Bone Morphogenetic Protein 7 - metabolism</subject><subject>Cell Line</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - metabolism</subject><subject>Gene Expression Regulation</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Kidney Tubules, Proximal - cytology</subject><subject>Kidney Tubules, Proximal - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Signal Transduction</subject><subject>Smad1 Protein - genetics</subject><subject>Smad1 Protein - metabolism</subject><subject>Smad5 Protein - genetics</subject><subject>Smad5 Protein - metabolism</subject><subject>Smad8 Protein - genetics</subject><subject>Smad8 Protein - metabolism</subject><subject>Surface Plasmon Resonance</subject><issn>0264-6021</issn><issn>1470-8728</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkD1PwzAURS0EoqWw8AOQx4IUsJ3nj460ggIqggEWlshJXiAosYudIvXfk0KB6d3h6Oq8S8gxZ-ecgbiY3gnGgWnNd8iQg2aJ0cLskiETChLFBB-Qgxjf2YYCtk8GQqbaMAlD8jIP2Da143QZsMKArqtt06xpXrsy0s7T3DukrQ_LN_-KDru66FHfYe0SQcfT-8dEnFLrSrqJQP0nhu-oD8leZZuIR9s7Is_XV0-zm2TxML-dXS6SAlLWJVqLiRAV9GrKCoBKTrjVaKwqJBdQllWaGsEmUubG9NqlgSJXldJmwgCVTkdk_NPba32sMHZZW8cCm8Y69KuYcSUFSEgV69GzH7QIPsb-4WwZ6taGdcZZttky-9-yh0-2vau8xfIP_R0v_QJPvmnw</recordid><startdate>20150215</startdate><enddate>20150215</enddate><creator>Church, Rachel H</creator><creator>Krishnakumar, Arjun</creator><creator>Urbanek, Annika</creator><creator>Geschwindner, Stefan</creator><creator>Meneely, Julie</creator><creator>Bianchi, Alessandro</creator><creator>Basta, Barbro</creator><creator>Monaghan, Sean</creator><creator>Elliot, Christopher</creator><creator>Strömstedt, Maria</creator><creator>Ferguson, Neil</creator><creator>Martin, Finian</creator><creator>Brazil, Derek P</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150215</creationdate><title>Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7</title><author>Church, Rachel H ; Krishnakumar, Arjun ; Urbanek, Annika ; Geschwindner, Stefan ; Meneely, Julie ; Bianchi, Alessandro ; Basta, Barbro ; Monaghan, Sean ; Elliot, Christopher ; Strömstedt, Maria ; Ferguson, Neil ; Martin, Finian ; Brazil, Derek P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-772922f44046a244f591a7e8a6c5124ddf33820955b88378d84cb6f678904e673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Bone Morphogenetic Protein 2 - genetics</topic><topic>Bone Morphogenetic Protein 2 - metabolism</topic><topic>Bone Morphogenetic Protein 4 - genetics</topic><topic>Bone Morphogenetic Protein 4 - metabolism</topic><topic>Bone Morphogenetic Protein 7 - genetics</topic><topic>Bone Morphogenetic Protein 7 - metabolism</topic><topic>Cell Line</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - metabolism</topic><topic>Gene Expression Regulation</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Kidney Tubules, Proximal - cytology</topic><topic>Kidney Tubules, Proximal - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Signal Transduction</topic><topic>Smad1 Protein - genetics</topic><topic>Smad1 Protein - metabolism</topic><topic>Smad5 Protein - genetics</topic><topic>Smad5 Protein - metabolism</topic><topic>Smad8 Protein - genetics</topic><topic>Smad8 Protein - metabolism</topic><topic>Surface Plasmon Resonance</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Church, Rachel H</creatorcontrib><creatorcontrib>Krishnakumar, Arjun</creatorcontrib><creatorcontrib>Urbanek, Annika</creatorcontrib><creatorcontrib>Geschwindner, Stefan</creatorcontrib><creatorcontrib>Meneely, Julie</creatorcontrib><creatorcontrib>Bianchi, Alessandro</creatorcontrib><creatorcontrib>Basta, Barbro</creatorcontrib><creatorcontrib>Monaghan, Sean</creatorcontrib><creatorcontrib>Elliot, Christopher</creatorcontrib><creatorcontrib>Strömstedt, Maria</creatorcontrib><creatorcontrib>Ferguson, Neil</creatorcontrib><creatorcontrib>Martin, Finian</creatorcontrib><creatorcontrib>Brazil, Derek P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Church, Rachel H</au><au>Krishnakumar, Arjun</au><au>Urbanek, Annika</au><au>Geschwindner, Stefan</au><au>Meneely, Julie</au><au>Bianchi, Alessandro</au><au>Basta, Barbro</au><au>Monaghan, Sean</au><au>Elliot, Christopher</au><au>Strömstedt, Maria</au><au>Ferguson, Neil</au><au>Martin, Finian</au><au>Brazil, Derek P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7</atitle><jtitle>Biochemical journal</jtitle><addtitle>Biochem J</addtitle><date>2015-02-15</date><risdate>2015</risdate><volume>466</volume><issue>1</issue><spage>55</spage><epage>68</epage><pages>55-68</pages><issn>0264-6021</issn><eissn>1470-8728</eissn><abstract>Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during diabetic nephropathy (DN) has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. In the present study, we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK (human embryonic kidney)-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readouts, Grem1 consistently demonstrated a higher affinity for BMP-2>BMP-4>BMP-7. Cell-associated Grem1 did not inhibit BMP-2- or BMP-4-mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.</abstract><cop>England</cop><pmid>25378054</pmid><doi>10.1042/BJ20140771</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Biochemical journal, 2015-02, Vol.466 (1), p.55-68 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Bone Morphogenetic Protein 2 - genetics Bone Morphogenetic Protein 2 - metabolism Bone Morphogenetic Protein 4 - genetics Bone Morphogenetic Protein 4 - metabolism Bone Morphogenetic Protein 7 - genetics Bone Morphogenetic Protein 7 - metabolism Cell Line Epithelial Cells - cytology Epithelial Cells - metabolism Gene Expression Regulation HEK293 Cells Humans Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Kidney Tubules, Proximal - cytology Kidney Tubules, Proximal - metabolism Phosphorylation Protein Binding Signal Transduction Smad1 Protein - genetics Smad1 Protein - metabolism Smad5 Protein - genetics Smad5 Protein - metabolism Smad8 Protein - genetics Smad8 Protein - metabolism Surface Plasmon Resonance |
| title | Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7 |
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