Specific structural features of heparan sulfate proteoglycans potentiate neuregulin-1 signaling.

2.50
Hdl Handle:
http://hdl.handle.net/10541/75662
Title:
Specific structural features of heparan sulfate proteoglycans potentiate neuregulin-1 signaling.
Authors:
Pankonin, Mark S; Gallagher, John T; Loeb, Jeffrey A
Abstract:
Neuregulins are a family of growth and differentiation factors that act through activation of cell-surface erbB receptor tyrosine kinases and have essential functions both during development and on the growth of cancer cells. One alternatively spliced neuregulin-1 form has a distinct heparin-binding immunoglobulin-like domain that enables it to adhere to heparan sulfate proteoglycans at key locations during development and substantially potentiates its activity. We examined the structural specificity needed for neuregulin-1-heparin interactions using a gel mobility shift assay together with an assay that measures the ability of specific oligosaccharides to block erbB receptor phosphorylation in L6 muscle cells. Whereas the N-sulfate group of heparin was most important, the 2-O-sulfate and 6-O-sulfate groups also contributed to neuregulin-1 binding in these two assays. Optimal binding to neuregulin-1 required eight or more heparin disaccharides; however, as few as two disaccharides were still able to bind neuregulin-1 to a lesser extent. The physiological importance of this specificity was shown both by chemical and siRNA treatment of cultured muscle cells. Pretreatment of muscle cells with chlorate that blocks all sulfation or with an siRNA that selectively blocks N-sulfation significantly reduced erbB receptor activation by neuregulin-1 but had no effect on the activity of neuregulin-1 that lacks the heparin-binding domain. These results suggest that the regulation of glycosaminoglycan sulfation is an important biological mechanism that can modulate both the localization and potentiation of neuregulin-1 signaling.
Affiliation:
Department of Neurology, Wayne State University, Detroit, Michigan 48201, USA.
Citation:
Specific structural features of heparan sulfate proteoglycans potentiate neuregulin-1 signaling. 2005, 280 (1):383-8 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
7-Jan-2005
URI:
http://hdl.handle.net/10541/75662
DOI:
10.1074/jbc.M402645200
PubMed ID:
15528194
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPankonin, Mark S-
dc.contributor.authorGallagher, John T-
dc.contributor.authorLoeb, Jeffrey A-
dc.date.accessioned2009-07-24T15:37:27Z-
dc.date.available2009-07-24T15:37:27Z-
dc.date.issued2005-01-07-
dc.identifier.citationSpecific structural features of heparan sulfate proteoglycans potentiate neuregulin-1 signaling. 2005, 280 (1):383-8 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid15528194-
dc.identifier.doi10.1074/jbc.M402645200-
dc.identifier.urihttp://hdl.handle.net/10541/75662-
dc.description.abstractNeuregulins are a family of growth and differentiation factors that act through activation of cell-surface erbB receptor tyrosine kinases and have essential functions both during development and on the growth of cancer cells. One alternatively spliced neuregulin-1 form has a distinct heparin-binding immunoglobulin-like domain that enables it to adhere to heparan sulfate proteoglycans at key locations during development and substantially potentiates its activity. We examined the structural specificity needed for neuregulin-1-heparin interactions using a gel mobility shift assay together with an assay that measures the ability of specific oligosaccharides to block erbB receptor phosphorylation in L6 muscle cells. Whereas the N-sulfate group of heparin was most important, the 2-O-sulfate and 6-O-sulfate groups also contributed to neuregulin-1 binding in these two assays. Optimal binding to neuregulin-1 required eight or more heparin disaccharides; however, as few as two disaccharides were still able to bind neuregulin-1 to a lesser extent. The physiological importance of this specificity was shown both by chemical and siRNA treatment of cultured muscle cells. Pretreatment of muscle cells with chlorate that blocks all sulfation or with an siRNA that selectively blocks N-sulfation significantly reduced erbB receptor activation by neuregulin-1 but had no effect on the activity of neuregulin-1 that lacks the heparin-binding domain. These results suggest that the regulation of glycosaminoglycan sulfation is an important biological mechanism that can modulate both the localization and potentiation of neuregulin-1 signaling.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshBinding Sites-
dc.subject.meshCell Line-
dc.subject.meshHeparan Sulfate Proteoglycans-
dc.subject.meshHeparin-
dc.subject.meshNeuregulin-1-
dc.subject.meshPhosphorylation-
dc.subject.meshProtein Binding-
dc.subject.meshRNA, Small Interfering-
dc.subject.meshRats-
dc.subject.meshReceptor, Epidermal Growth Factor-
dc.subject.meshSignal Transduction-
dc.subject.meshStructure-Activity Relationship-
dc.subject.meshSulfates-
dc.titleSpecific structural features of heparan sulfate proteoglycans potentiate neuregulin-1 signaling.en
dc.typeArticleen
dc.contributor.departmentDepartment of Neurology, Wayne State University, Detroit, Michigan 48201, USA.en
dc.identifier.journalThe Journal of Biological Chemistryen

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