The molecular phenotype of heparan sulfate in the Hs2st-/- mutant mouse
The molecular phenotype of heparan sulfate in the Hs2st-/- mutant mouse
复制标题
DOI：
10.1074/jbc.m100379200
复制
发表时间：
2001-09-21
影响因子：
4.8
通讯作者：
Gallagher, JT
中科院分区：
文献类型：
--
作者：
Merry, CLR;Bullock, SL;Gallagher, JT
硫酸乙酰肝素（HS）是许多生长因子、形态发生素和粘附蛋白的共受体。HS生物合成修饰可以决定HS-配体相互作用的强度和结果。我们先前描述了小鼠的表型与基因陷阱突变Hs 2st，编码关键HS 2-O-磺基转移酶在HS聚合物修饰。与缺乏HS的胚胎的早期发育失败相反，Hs 2st（-/-）小鼠的异常仅发生在妊娠中期后，最引人注目的是肾脏发育的完全失败。在突变体HS中未检测到脲酸2-O-硫酸盐，表明Hs 2st功能完全丧失。然而，突变体HS的结构域结构是保守的，并且N-和6-O-硫酸化的补偿性增加维持了总体电荷密度。突变体HS对肝细胞生长因子/分散因子和纤连蛋白的表观亲和力不变，但对成纤维细胞生长因子-1和-2的亲和力降低。令人惊讶的是，Hs 2st（-/-）细胞能够对成纤维细胞生长因子-1和-2以及对肝细胞生长因子/分散因子产生明显正常的信号传导应答。
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.