Ivanisevic Ljubica, Banerjee Kris, Saragovi H Uri
Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
Oncogene. 2003 Aug 28;22(36):5677-85. doi: 10.1038/sj.onc.1206864.
The neurotrophins neurotrophin-3 (NT-3), brain-derived growth factor (BDNF) and nerve growth factor (NGF) bind to the p75 receptor, but each neurotrophin also binds a more selective Trk receptor (e.g. TrkA-NGF and TrkC-NT-3). The biochemical signals following engagement of either Trk or p75 with ligands are well understood, but long-term biological outcomes (trophic, proapoptotic or differentiative) remain unclear because they are cell/tissue specific. For example, Trk receptors are usually trophic but when overexpressed they can be proapoptotic in neuroblastomas and medulloblastomas. We hypothesized that coexpression of Trk and p75 receptors may lead to cross-regulation of signals and different biological outcomes; and used receptor-selective ligands to study cross-regulation by these receptors. We show that in the absence of Trk activation, expression of TrkC is permissive of p75 trophic and differentiation signals induced by p75 ligands, whereas expression of TrkA abolishes trophic and differentiation signals induced by p75 ligands. In contrast, in the presence of Trk activation, p75 ligands can regulate TrkA-mediated survival and TrkC-mediated differentiation. Therefore, a complex homeostasis of p75-selective and Trk-selective signals may determine the fate of cells expressing both receptors.
神经营养因子-3（NT-3）、脑源性神经营养因子（BDNF）和神经生长因子（NGF）可与p75受体结合，但每种神经营养因子也会结合一种更具选择性的Trk受体（如TrkA与NGF结合、TrkC与NT-3结合）。Trk或p75与配体结合后的生化信号已为人熟知，但长期的生物学结果（营养作用、促凋亡作用或分化作用）仍不明确，因为这些结果具有细胞/组织特异性。例如，Trk受体通常具有营养作用，但在过表达时，它们在神经母细胞瘤和髓母细胞瘤中可能具有促凋亡作用。我们推测Trk和p75受体的共表达可能导致信号的交叉调节和不同的生物学结果；并使用受体选择性配体来研究这些受体的交叉调节作用。我们发现，在没有Trk激活的情况下，TrkC的表达允许p75配体诱导的p75营养和分化信号，而TrkA的表达则消除了p75配体诱导的营养和分化信号。相反，在有Trk激活的情况下，p75配体可以调节TrkA介导的存活和TrkC介导的分化。因此，p75选择性信号和Trk选择性信号之间复杂的稳态可能决定同时表达这两种受体的细胞的命运。
