Individual and combined effects of TrkA and p75NTR nerve growth factor receptors -: A role for the high affinity receptor site
Individual and combined effects of TrkA and p75NTR nerve growth factor receptors -: A role for the high affinity receptor site
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DOI：
10.1074/jbc.m212270200
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发表时间：
2003-07-04
影响因子：
4.8
通讯作者：
Neet, KE
中科院分区：
文献类型：
--
作者：
Lad, SP;Peterson, DA;Neet, KE
神经营养因子信号转导中的一个长期存在的问题是异聚TrkA-p75（NTR）复合物是否具有与单独的同源寡聚TrkA或p75（NTR）显著不同的信号传导能力。为了解决这个问题，表达血小板衍生的生长因子受体-TrkA嵌合体和p75（NTR）选择性神经生长因子突变体（Delta 9/13 NGF）的转染的PC 12细胞的各种组合分别用于选择性刺激TrkA或p75（NTR）信号传导。在下游信号传导和某些终点方面分析了单个和组合受体效应的贡献。结果表明，高亲和力异聚体NGF受体位点的两个独特功能：（a）在NGF诱导的神经突生长的产生中整合MAPK和Akt途径，以及（B）Akt途径的快速和持续激活，从而导致细胞长期存活。尽管TrkA信号的激活足以引发PC 12细胞中的神经突生长，但通过p75（NTR）的信号传导起着调节作用，特别是在精细的突触“终扣样”结构的形成增加中，其中TrkA和p75（NTR）似乎共定位。此外，TrkA/p75（NTR）异聚体受体信号转导网络中的一种新的相互作用被揭示，即NGF诱导的MAPK通路的激活似乎抑制了平行的NGF诱导的Akt通路。
A long-standing question in neurotrophin signal transduction is whether heteromeric TrkA-p75(NTR) complexes possess signaling capabilities that are significantly different from homo-oligomeric TrkA or p75(NTR) alone. To address this issue, various combinations of transfected PC12 cells expressing a platelet-derived growth factor receptor-TrkA chimera and the p75(NTR)-selective nerve growth factor mutant (Delta9/13 NGF) were utilized to selectively stimulate TrkA or p75(NTR) signaling, respectively. The contribution of individual and combined receptor effects was analyzed in terms of downstream signaling and certain end points. The results suggest two unique functions for the high affinity heteromeric NGF receptor site: ( a) integration of both the MAPK and Akt pathways in the production of NGF-induced neurite outgrowth, and (b) rapid and sustained activation of the Akt pathway, with consequent long term cellular survival. Whereas activation of TrkA signaling is sufficient for eliciting neurite outgrowth in PC12 cells, signaling through p75(NTR) plays a modulatory role, especially in the increased formation of fine, synaptic "bouton-like" structures, in which both TrkA and p75(NTR) appear to co-localize. In addition, a new interaction in the TrkA/p75(NTR) heteromeric receptor signal transduction network was revealed, namely that NGF-induced activation of the MAPK pathway appears to inhibit the parallel NGF-induced Akt pathway.