Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation
Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation
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DOI：
10.1074/jbc.m504163200
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发表时间：
2006-01-13
影响因子：
4.8
通讯作者：
Chao, MV
中科院分区：
文献类型：
--
作者：
Arévolo, JC;Pereira, DB;Chao, MV
神经营养因子（例如神经生长因子和脑源性神经营养因子）通过细胞表面的受体二聚化，然后自磷酸化和招募细胞内信号分子来激活Trk受体酪氨酸激酶。神经营养因子使用的细胞内途径共享许多由其他受体酪氨酸激酶（RTK）使用的共同蛋白质底物，如Shc、Grb 2、FRS 2和磷脂酶C-γ。在这里，我们描述了一种新的RTK机制，涉及220千道尔顿的膜四跨膜蛋白，ARMS/Kidins 220，这是迅速酪氨酸磷酸化后，神经营养因子治疗的原代神经元。ARMS/Kidins 220经历多个酪氨酸磷酸化事件，也经历蛋白激酶D的丝氨酸磷酸化。我们已经确定了一个单一的酪氨酸（Tyr 1096）磷酸化事件在ARMS/Kidins 220中发挥关键作用的神经营养信号。ARMS/Kidins 220和CrkL（C3 G-Rap 1-MAP激酶级联的上游组分）的重组复合物是SH 3依赖性的。然而，Tyr 1096磷酸化使ARMS/Kidins 220能够通过其SH 2结构域募集CrkL，从而释放CrkL SH 3结构域以神经营养因子依赖性方式与C3 G接合以激活MAP激酶。因此，Tyr 1096的突变消除了CrkL相互作用并维持了MAPK激酶活性，这是在其他RTK中通常观察不到的反应。因此，Trk受体信号传导涉及通过非常规底物的诱导型开关机制，该机制将神经营养因子的作用与其他生长因子受体区分开来。
Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and recruitment of intracellular signaling molecules. The intracellular pathways used by neurotrophins share many common protein substrates that are used by other receptor tyrosine kinases (RTK), such as Shc, Grb2, FRS2, and phospholipase C-gamma. Here we describe a novel RTK mechanism that involves a 220-kilodalton membrane tetraspanning protein, ARMS/Kidins220, which is rapidly tyrosine phosphorylated in primary neurons after neurotrophin treatment. ARMS/Kidins220 undergoes multiple tyrosine phosphorylation events and also serine phosphorylation by protein kinase D. We have identified a single tyrosine (Tyr1096) phosphorylation event in ARMS/Kidins220 that plays a critical role in neurotrophin signaling. A reassembled complex of ARMS/Kidins220 and CrkL, an upstream component of the C3G-Rap1-MAP kinase cascade, is SH3-dependent. However, Tyr1096 phosphorylation enables ARMS/Kidins220 to recruit CrkL through its SH2 domain, thereby freeing the CrkL SH3 domain to engage C3G for MAP kinase activation in a neurotrophin dependent manner. Accordingly, mutation of Tyr1096 abolished CrkL interaction and sustained MAPK kinase activity, a response that is not normally observed in other RTKs. Therefore, Trk receptor signaling involves an inducible switch mechanism through an unconventional substrate that distinguishes neurotrophin action from other growth factor receptors.