2-O Heparan Sulfate Sulfation by Hs2st Is Required for Erk/Mapk Signalling Activation at the Mid-Gestational Mouse Telencephalic Midline.
2-O Heparan Sulfate Sulfation by Hs2st Is Required for Erk/Mapk Signalling Activation at the Mid-Gestational Mouse Telencephalic Midline.
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DOI：
10.1371/journal.pone.0130147
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pratt T
中科院分区：
文献类型：
--
作者：
Chan WK;Howe K;Clegg JM;Guimond SE;Price DJ;Turnbull JE;Pratt T
硫酸乙酰肝素（HS）是一种线性碳水化合物，由聚合的糖醛酸-葡糖胺二糖单元组成，可装饰细胞表面并分泌细胞外基质中的糖蛋白。在哺乳动物中，HS通过15种不同的乙酰肝素磺基转移酶（HST）进行差异硫酸化，其中Hs 2st独特地催化HS中糖醛酸的2-O位置的硫酸化。HS硫酸化被认为是通过促进HS与信号传导蛋白的相互作用而对信号传导途径的调节是重要的，所述信号传导蛋白包括成纤维细胞生长因子（Fgf）家族的那些，所述成纤维细胞生长因子（Fgf）家族通过细胞外信号调节激酶Erk 1/2的磷酸化而发出信号。在发育中的小鼠端脑中，Fgf 2信号调节增殖和神经发生。Hs 2st功能的丧失表现为Fgf 2或Erk 1/2功能被废除的突变小鼠大脑皮层变薄，这表明2-O-硫酸化HS结构在体内Fgf 2/Erk信号通路中起特定作用的假设。本研究探讨了在E12.5小鼠胚胎发育中期，2-O硫酸化在端脑中线发育中Fgf 2/Erk信号传导中的分子作用。我们检测了野生型和Hs 2st-/-小鼠中Hs 2st、Fgf 2和Erk 1/2活性的表达。我们发现Hs 2st在中线高水平表达，与高水平的Erk 1/2激活相关，并且Erk 1/2激活在Hs 2st-/-突变体中在头端脑中线处显著降低。我们还发现，2-O硫酸化是特别需要的FGF 2蛋白FGFR 1，其主要的细胞表面受体在吻端脑中线的结合。我们的结论是，2-O硫酸化HS的结构所产生的Hs 2st需要形成生产性的信号复合物之间的HS，Fgf 2和Fgfr 1激活Erk 1/2的中线。总的来说，我们的数据表明了一种有趣的可能性，即Hs 2st的差异表达通过增加细胞对更广泛的Fgf 2信号的敏感性来靶向头端脑中线的高水平Erk信号传导。
Heparan sulfate (HS) is a linear carbohydrate composed of polymerized uronate-glucosamine disaccharide units that decorates cell surface and secreted glycoproteins in the extracellular matrix. In mammals HS is subjected to differential sulfation by fifteen different heparan sulfotransferase (HST) enzymes of which Hs2st uniquely catalyzes the sulfation of the 2-O position of the uronate in HS. HS sulfation is postulated to be important for regulation of signaling pathways by facilitating the interaction of HS with signaling proteins including those of the Fibroblast Growth Factor (Fgf) family which signal through phosphorylation of extracellular signal-regulated kinases Erk1/2. In the developing mouse telencephalon Fgf2 signaling regulates proliferation and neurogenesis. Loss of Hs2st function phenocopies the thinned cerebral cortex of mutant mice in which Fgf2 or Erk1/2 function are abrogated, suggesting the hypothesis that 2-O-sulfated HS structures play a specific role in Fgf2/Erk signaling pathway in this context in vivo. This study investigated the molecular role of 2-O sulfation in Fgf2/Erk signaling in the developing telencephalic midline midway through mouse embryogenesis at E12.5. We examined the expression of Hs2st, Fgf2, and Erk1/2 activity in wild-type and Hs2st-/- mice. We found that Hs2st is expressed at high levels at the midline correlating with high levels of Erk1/2 activation and Erk1/2 activation was drastically reduced in the Hs2st-/- mutant at the rostral telencephalic midline. We also found that 2-O sulfation is specifically required for the binding of Fgf2 protein to Fgfr1, its major cell-surface receptor at the rostral telencephalic midline. We conclude that 2-O sulfated HS structures generated by Hs2st are needed to form productive signaling complexes between HS, Fgf2 and Fgfr1 that activate Erk1/2 at the midline. Overall, our data suggest the interesting possibility that differential expression of Hs2st targets the rostral telencephalic midline for high levels of Erk signaling by increasing the sensitivity of cells to an Fgf2 signal that is rather more widespread.
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DOI：
10.1074/jbc.m109.032755
发表时间：
2009-09-18
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Guimond SE;Puvirajesinghe TM;Skidmore MA;Kalus I;Dierks T;Yates EA;Turnbull JE
通讯作者：
Turnbull JE
影响因子：
4.8
作者：
Qu, Xiuxia;Carbe, Christian;Zhang, Xin
通讯作者：
Zhang, Xin
影响因子：
16.2
作者：
Sahara, Setsuko;O'Leary, Dennis D. M.
通讯作者：
O'Leary, Dennis D. M.
影响因子：
4.8
作者：
Merry, CLR;Bullock, SL;Gallagher, JT
通讯作者：
Gallagher, JT
影响因子：
5.3
作者：
Clegg, James M.;Conway, Christopher D.;Pratt, Thomas
通讯作者：
Pratt, Thomas