Heparan sulfate proteoglycans are ligands for receptor protein tyrosine phosphatase σ
Heparan sulfate proteoglycans are ligands for receptor protein tyrosine phosphatase σ
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DOI：
10.1128/mcb.22.6.1881-1892.2002
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发表时间：
2002-03-01
影响因子：
5.3
通讯作者：
Stoker, AW
中科院分区：
文献类型：
--
作者：
Aricescu, AR;McKinnell, IW;Stoker, AW
RPTPalpha是一种参与神经系统发育的细胞粘附分子样受体蛋白酪氨酸磷酸酶。它的鸟类直系同源物，称为cPTPsigma或cPTPpalpha，促进视网膜内轴突生长并控制生长锥的形态。cPTPsigma功能的分子机制仍有待确定，因为它的生理配体和底物都没有被描述。然而，一个主要类别的配体存在于视网膜基底层和神经胶质终足中，视网膜轴突的有效天然生长基质。我们在这里证明，cPTPsigma是一种肝素结合蛋白，其基底层配体包括硫酸乙酰肝素蛋白聚糖（HSPGs）聚集蛋白和胶原蛋白XVIII。这些分子在体外以高亲和力与cPTPsigma相互作用，并且这种结合完全依赖于它们的硫酸乙酰肝素链。使用分子建模和定点诱变，在cPTPsigma的第一个免疫球蛋白样结构域中鉴定了肝素和硫酸乙酰肝素的结合位点。因此，HSPG是cPTPsigma的一类新型异型配体，表明轴突和生长锥中的cPTPsigma信号传导直接响应于基质相关的线索。
RPTPalpha is a cell adhesion molecule-like receptor protein tyrosine phosphatase involved in nervous system development. Its avian orthologue, known as cPTPsigma or CRYPalpha, promotes intraretinal axon growth and controls the morphology of growth cones. The molecular mechanisms underlying the functions of cPTPsigma are still to be determined, since neither its physiological ligand(s) nor its substrates have been described. Nevertheless, a major class of ligand(s) is present in the retinal basal lamina and glial endfeet, the potent native growth substrate for retinal axons. We demonstrate here that cPTPsigma is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (HSPGs) agrin and collagen XVIII. These molecules interact with high affinity with cPTPsigma in vitro, and this binding is totally dependent upon their heparan sulfate chains. Using molecular modelling and site-directed mutagenesis, a binding site for heparin and heparan sulfate was identified in the first immunoglobulin-like domain of cPTPsigma. HSPGs are therefore a novel class of heterotypic ligand for cPTPsigma, suggesting that cPTPsigma signaling in axons and growth cones is directly responsive to matrix-associated cues.