Role of Chondroitin Sulfate ( CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity PLEIOTROPHIN-PTPRZ-A SIGNALING IS INVOLVED IN OLIGODENDROCYTE DIFFERENTIATION
Role of Chondroitin Sulfate ( CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity PLEIOTROPHIN-PTPRZ-A SIGNALING IS INVOLVED IN OLIGODENDROCYTE DIFFERENTIATION
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DOI：
10.1074/jbc.m116.742536
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发表时间：
2016-08-26
影响因子：
4.8
通讯作者：
Noda, Masaharu
中科院分区：
文献类型：
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作者：
Kuboyama, Kazuya;Fujikawa, Akihiro;Noda, Masaharu
Z 型蛋白酪氨酸磷酸酶受体 (PTPRZ) 在发育中的大脑中主要以 CS 蛋白聚糖的形式表达。 PTPRZ通过选择性剪接而具有长型(PTPRZ-A)和短型(PTPRZ-B)受体形式。 PTPRZ 的胞外 CS 部分是与抑制性配体（如多效素 (PTN)、中期因子和白细胞介素 34）高亲和力结合所必需的；然而，其在调节 PTPRZ 活性方面的功能意义仍不清楚。我们在此发现CS修饰的PTPRZ-A的蛋白表达开始较早，大约在出生后5-10天（P5-P10）达到峰值，然后PTN的蛋白表达在对应于小鼠大脑中髓鞘形成开始的发育阶段的P10处达到峰值。与野生型小鼠相比，Ptn 缺陷小鼠始终表现出髓磷脂碱性蛋白（髓磷脂鞘的主要成分）的表达开始较晚。应用配体后，培养的少突胶质细胞前体细胞中的 PTPRZ-A/B 在细胞表面呈现点状定位而不是弥散分布，导致 PTPRZ 失活和少突胶质细胞分化。用软骨素酶 ABC 去除 CS 链，但用抗 PTPRZ 胞外结构域的多克隆抗体去除 CS 链时，观察到了相同的效果。这些结果表明，带负电的 CS 部分阻止 PTPRZ 自发聚集，而带正电的配体 PTN 可能通过中和 CS 链之间的静电排斥来诱导 PTPRZ 聚集。总而言之，这些数据表明 PTN-PTPRZ-A 信号传导控制体内少突胶质细胞前体细胞分化的时间，其中 PTPRZ 受体的 CS 部分将它们维持在单体活性状态，直到其配体结合。
Protein-tyrosine phosphatase receptor type Z (PTPRZ) is predominantly expressed in the developing brain as a CS proteoglycan. PTPRZ has long (PTPRZ-A) and short type (PTPRZ-B) receptor forms by alternative splicing. The extracellular CS moiety of PTPRZ is required for high-affinity binding to inhibitory ligands, such as pleiotrophin (PTN), midkine, and interleukin-34; however, its functional significance in regulating PTPRZ activity remains obscure. We herein found that protein expression of CS-modified PTPRZ-A began earlier, peaking at approximately postnatal days 5-10 (P5-P10), and then that of PTN peaked at P10 at the developmental stage corresponding to myelination onset in the mouse brain. Ptn-deficient mice consistently showed a later onset of the expression of myelin basic protein, a major component of the myelin sheath, than wild-type mice. Upon ligand application, PTPRZ-A/B in cultured oligodendrocyte precursor cells exhibited punctate localization on the cell surface instead of diffuse distribution, causing the inactivation of PTPRZ and oligodendrocyte differentiation. The same effect was observed with the removal of CS chains with chondroitinase ABC but not polyclonal antibodies against the extracellular domain of PTPRZ. These results indicate that the negatively charged CS moiety prevents PTPRZ from spontaneously clustering and that the positively charged ligand PTN induces PTPRZ clustering, potentially by neutralizing electrostatic repulsion between CS chains. Taken altogether, these data indicate that PTN-PTPRZ-A signaling controls the timing of oligodendrocyte precursor cell differentiation in vivo, in which the CS moiety of PTPRZ receptors maintains them in a monomeric active state until its ligand binding.