Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin.
Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin.
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DOI：
10.1083/jcb.201009136
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发表时间：
2011-01-10
期刊：
影响因子：
--
通讯作者：
Saarma M
中科院分区：
文献类型：
--
作者：
Bespalov MM;Sidorova YA;Tumova S;Ahonen-Bishopp A;Magalhães AC;Kulesskiy E;Paveliev M;Rivera C;Rauvala H;Saarma M
Syndecan-3可能单独或作为RET的辅助受体，通过GNDF、NRTN和ARTN促进皮质神经元的细胞扩散、神经突生长和迁移。神经胶质细胞系来源的神经营养因子（GDNF）家族配体（GFLs）是多巴胺能神经元和运动神经元的有效存活因子，具有治疗帕金森病的潜力。可溶性GFLs与配体特异性糖基磷脂酰肌醇锚定的辅助受体（GDNF家族受体α）结合，并通过受体酪氨酸激酶RET发出信号。在本文中，我们发现除了persephin外，所有固定化的基质结合GFLs都使用一种完全不同的受体。它们与syndecan-3相互作用，syndecan-3是一种跨膜硫酸肝素（HS）蛋白多糖，通过高亲和力结合到其HS链上。GFL-syndecan-3相互作用介导细胞扩散和神经突生长，参与Src激酶激活。GDNF以syndecan-3依赖性的方式促进皮质神经元的迁移，与此一致的是，缺乏syndecan-3或GDNF的小鼠皮质γ-氨基丁酸释放神经元数量减少，这表明这两种分子在皮质发育中起核心作用。总的来说，syndecan-3可以直接转导GFL信号或作为辅助受体，将GFL传递给信号受体RET。
Syndecan-3 may act alone or as a coreceptor with RET to promote cell spreading, neurite outgrowth, and migration of cortical neurons by GNDF, NRTN, and ARTN. Glial cell line–derived neurotrophic factor (GDNF) family ligands (GFLs) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson’s disease. Soluble GFLs bind to a ligand-specific glycosylphosphatidylinositol-anchored coreceptor (GDNF family receptor α) and signal through the receptor tyrosine kinase RET. In this paper, we show that all immobilized matrix-bound GFLs, except persephin, use a fundamentally different receptor. They interact with syndecan-3, a transmembrane heparan sulfate (HS) proteoglycan, by binding to its HS chains with high affinity. GFL–syndecan-3 interaction mediates both cell spreading and neurite outgrowth with the involvement of Src kinase activation. GDNF promotes migration of cortical neurons in a syndecan-3–dependent manner, and in agreement, mice lacking syndecan-3 or GDNF have a reduced number of cortical γ-aminobutyric acid–releasing neurons, suggesting a central role for the two molecules in cortical development. Collectively, syndecan-3 may directly transduce GFL signals or serve as a coreceptor, presenting GFLs to the signaling receptor RET.
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