Protein tyrosine phosphatase receptor type Z dephosphorylates TrkA receptors and attenuates NGF-dependent neurite outgrowth of PC12 cells
Protein tyrosine phosphatase receptor type Z dephosphorylates TrkA receptors and attenuates NGF-dependent neurite outgrowth of PC12 cells
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DOI：
10.1093/jb/mvn064
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发表时间：
2008-08-01
影响因子：
2.7
通讯作者：
Noda, Masaharu
中科院分区：
文献类型：
--
作者：
Shintani, Takafumi;Noda, Masaharu
蛋白酪氨酸磷酸酶受体Z型（Ptprz/Ptp zeta/RPTP beta）是一种主要在中枢神经系统中表达的受体样蛋白酪氨酸磷酸酶（RPTP）。原肌球蛋白相关激酶（Trks）是在发育中的神经系统中高度表达的单程跨膜分子。在神经营养因子的配体结合后，Trk受体通过酪氨酸残基的自磷酸化被激活;然而，负责Trk受体的负调节的PTP尚未完全阐明。在这里，我们确定Ptprz作为一个特定的PTP，有效地去磷酸化作为底物的TrkA。Ptprz与Trk受体在293 T细胞中的共表达表明Ptprz抑制TrkA的配体非依赖性酪氨酸磷酸化，但不抑制TrkB或TrkC的酪氨酸磷酸化，并且Ptprz减弱神经生长因子（NGF）诱导的TrkA活化。与TrkA突变体的共表达分析表明，Ptprz去磷酸化磷酸酪氨酸残基的激酶结构域的激活环，这是必要的激活的TrkA受体。与这些发现相一致，Ptprz在PC 12 D细胞中的强制表达显著抑制了由低剂量的NGF诱导的神经突延伸。此外，在Ptprz缺陷小鼠的脑中观察到TrkA的酪氨酸磷酸化的增量。因此，Ptprz似乎是调节TrkA受体的活化和信号传导的PTP之一。
Protein tyrosine phosphatase receptor type Z (Ptprz/Ptp zeta/RPTP beta) is a receptor-like protein tyrosine phosphatase (RPTP) which is predominantly expressed in the central nervous system. Tropomyosin-related kinases (Trks) are single-pass transmembrane molecules that are highly expressed in the developing nervous system. Upon the ligand binding of neurotrophins, Trk receptors are activated through autophosphorylation of tyrosine residues; however, the PTPs responsible for the negative regulation of Trk receptors have not been fully elucidated. Here, we identified Ptprz as a specific PTP that efficiently dephosphorylates TrkA as a substrate. Co-expression of Ptprz with Trk receptors in 293T cells showed that Ptprz suppresses the ligand-independent tyrosine phosphorylation of TrkA, but not of TrkB or TrkC, and that Ptprz attenuates TrkA activation induced by nerve growth factor (NGF). Co-expression analyses with TrkA mutants revealed that Ptprz dephosphorylates phosphotyrosine residues in the activation loop of the kinase domain, which are requisite for activation of the TrkA receptor. Consistent with these findings, forced expression of Ptprz in PC12D cells markedly inhibited neurite extension induced by a low dose of NGF. In addition, an increment in the tyrosine phosphorylation of TrkA was observed in the brain of Ptprz-deficient mice. Ptprz thus appears to be one of the PTPs which regulate the activation and signalling of TrkA receptors.