NDLI: Mutation in the Heparan Sulfate Biosynthesis Enzyme EXT1 Influences Growth Factor Signaling and Fibroblast Interactions with the Extracellular Matrix*

Content Provider	PubMed Central
Author	Österholm, Cecilia Barczyk, Malgorzata M. Busse, Marta Mona, Grønning Reed, Rolf K. Marion, Kusche-gullberg
Abstract	Heparan sulfate (HS) chains bind and modulate the signaling efficiency of many ligands, including members of the fibroblast growth factor (FGF) and platelet-derived growth factor families. We previously reported the structure of HS synthesized by embryonic fibroblasts from mice with a gene trap mutation of Ext1 that encodes a glycosyltransferase involved in HS chain elongation. The gene trap mutation results in low expression of Ext1, and, as a consequence, HS chain length is substantially reduced. In the present study, Ext1 mutant and wild-type mouse embryonic fibroblasts were analyzed for the functional consequences of the Ext1 mutation for growth factor signaling and interaction with the extracellular matrix. Here, we show that the phosphorylation of ERK1/2 in response to FGF2 stimulation was markedly decreased in the Ext1 mutant fibroblasts, whereas neither PDGF-BB nor FGF10 signaling was significantly affected. Furthermore, Ext1 mutants displayed reduced ability to attach to collagen I and to contract collagen lattices, even though no differences in the expression of collagen-binding integrins were observed. Reintroduction of Ext1in the Ext1 mutant fibroblasts rescued HS chain length, FGF2 signaling, and the ability of the fibroblasts to contract collagen. These data suggest that the length of the HS chains is a critical determinant of HS-protein interactions and emphasize the essential role of EXT1 in providing specific binding sites for growth factors and extracellular matrix proteins.
Related Links	http://dx.doi.org/10.1074/jbc.m109.005264
Ending Page	34943
Page Count	9
Starting Page	34935
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	50
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-12-11
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Mutation in the Heparan Sulfate Biosynthesis Enzyme EXT1 Influences Growth Factor Signaling and Fibroblast Interactions with the Extracellular Matrix

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Mutation in the Heparan Sulfate Biosynthesis Enzyme EXT1 Influences Growth Factor Signaling and Fibroblast Interactions with the Extracellular Matrix*

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