The molecular phenotype of heparan sulfate in the Hs2st-/- mutant mouse.
Heparan sulfate (HS) is a co-receptor for a number of growth factors, morphogens, and adhesion proteins. HS biosynthetic modifications may determine the strength and outcome of HS-ligand interactions. We previously described the phenotype of mice with a gene-trap mutation in Hs2st, encoding the key HS 2-O-sulfotransferase enzyme in HS polymer modification. In contrast to the early developmental failure of embryos lacking HS, the onset of abnormalities in the Hs2st(-/-) mice occurs only after midgestation, the most dramatic being the complete failure of kidney development. Uronate 2-O-sulfates were not detected in the mutant HS, indicating a complete loss of function of Hs2st. However, the domain structure of the mutant HS is conserved, and compensatory increases in N- and 6-O-sulfation maintain the overall charge density. The apparent affinities of the mutant HS for hepatocyte growth factor/scatter factor and fibronectin were unchanged but were reduced for fibroblast growth factor-1 and -2. Surprisingly, the Hs2st(-/-) cells were able to mount an apparently normal signaling response to fibroblast growth factor-1 and -2 as well as to hepatocyte growth factor/scatter factor.
Merry
C L
CL
Cancer Research Campaign Department of Medical Oncology, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom. cmerry@picr.man.ac.uk
Bullock
S L
SL
Swan
D C
DC
Backen
A C
AC
Lyon
M
M
Beddington
R S
RS
Wilson
V A
VA
Gallagher
J T
JT
D000818:Animals; D004187:Disaccharides / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006868:Hydrolysis; D051379:Mice; D008817:Mice, Mutant Strains; D009608:Nitrous Acid / Q000378:metabolism; D010641:Phenotype; D011133:Polysaccharide-Lyases / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000502:physiology*
D004187:Disaccharides; D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D017228:Hepatocyte Growth Factor; D009608:Nitrous Acid; D011133:Polysaccharide-Lyases; D015238:Sulfotransferases; C106358:heparan-sulfate 2-sulfotransferase; C021349:heparitinsulfate lyase