The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling
The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling
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DOI：
10.1242/jcs.062612
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发表时间：
2010-07-01
影响因子：
4
通讯作者：
Barker, Philip A.
中科院分区：
文献类型：
--
作者：
Ceni, Claire;Kommaddi, Reddy Peera;Barker, Philip A.
p75神经营养因子受体（p75 NTR）增强Trk信号传导，但潜在的机制仍然不确定。在这里，我们研究p75 NTR切割和Trk信号之间的关系。我们发现，在PC 12细胞中，神经生长因子（NGF）诱导快速和强大的α-分泌酶和γ-分泌酶依赖的裂解p75 NTR，释放所得的胞内结构域到胞质溶胶。脑源性神经营养因子在原代小脑颗粒神经元中同样诱导p75 NTR裂解。p75 NTR裂解通过MEK-Erk信号传导的Trk依赖性活化和α-分泌酶活性的诱导而发生，并且不依赖于配体与p75 NTR的结合。缺乏p75 NTR的神经元和PC 12细胞显示神经营养因子依赖性Akt激活缺陷。使用全长p75 NTR或p75胞内结构域拯救正常Akt活化，但不使用抗切割p75 NTR。然后，我们证明，神经生长因子依赖的生长停滞的PC 12细胞需要p75 NTR裂解和产生的细胞内结构域。我们的结论是可溶性p75 NTR胞内域的Trk诱导的切割的产生发挥了重要作用，在Trk依赖的信号事件。
The p75 neurotrophin receptor (p75NTR) potentiates Trk signaling, but the underlying mechanisms remain uncertain. Here, we examine the relationship between p75NTR cleavage and Trk signaling. We found that, in PC12 cells, nerve growth factor (NGF) induces rapid and robust alpha-secretase-and gamma-secretase-dependent cleavage of p75NTR, releasing the resulting intracellular domain into the cytosol. Brain-derived neurotrophic factor similarly induces p75NTR cleavage in primary cerebellar granule neurons. p75NTR cleavage occurs by means of Trk-dependent activation of MEK-Erk signaling and induction of alpha-secretase activity, and is independent of ligand binding to p75NTR. Neurons and PC12 cells lacking p75NTR display defects in neurotrophin-dependent Akt activation. Normal Akt activation is rescued using full-length p75NTR or the p75 intracellular domain, but not cleavage-resistant p75NTR. We then demonstrate that NGF-dependent growth arrest of PC12 cells requires p75NTR cleavage and generation of the intracellular domain. We conclude that generation of the soluble p75NTR intracellular domain by Trk-induced cleavage plays a fundamental role in Trk-dependent signaling events.