Differential cross-regulation of TrkA and TrkC tyrosine kinase receptors with p75

被引:34
作者
Ivanisevic, L
Banerjee, K
Saragovi, HU
机构
[1] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada
[2] McGill Univ, Oncol Canc Ctr, Montreal, PQ H3G 1Y6, Canada
基金
加拿大健康研究院;
关键词
receptor; neurotrophin; cross-regulation; ligand; Trk; signal transduction;
D O I
10.1038/sj.onc.1206864
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:5677 / 5685
页数:9
相关论文
共 49 条
[1]   The TrkB-Shc site signals neuronal survival and local axon growth via MEK and PI3-kinase [J].
Atwal, JK ;
Massie, B ;
Miller, FD ;
Kaplan, DR .
NEURON, 2000, 27 (02) :265-277
[2]   The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death [J].
Bamji, SX ;
Majdan, M ;
Pozniak, CD ;
Belliveau, DJ ;
Aloyz, R ;
Kohn, J ;
Causing, CG ;
Miller, FD .
JOURNAL OF CELL BIOLOGY, 1998, 140 (04) :911-923
[3]   p75NTR:: A study in contrasts [J].
Barker, PA .
CELL DEATH AND DIFFERENTIATION, 1998, 5 (05) :346-356
[4]   PC12nnr5 cells expressing TrkA receptors undergo morphological but not cholinergic phenotypic differentiation in response to nerve growth factor [J].
Baskey, JC ;
Kalisch, BE ;
Davis, WL ;
Meakin, SO ;
Rylett, RJ .
JOURNAL OF NEUROCHEMISTRY, 2002, 80 (03) :501-511
[5]   The p75 neurotrophin receptor (p75NTR) alters tumor necrosis factor-mediated NF-κB activity under physiological conditions, but direct p75NTR-mediated NF-κB activation requires cell stress [J].
Bhakar, AL ;
Roux, PP ;
Lachance, C ;
Kryl, D ;
Zeindler, C ;
Barker, PA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (30) :21443-21449
[6]   Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR [J].
Bibel, M ;
Hoppe, E ;
Barde, YA .
EMBO JOURNAL, 1999, 18 (03) :616-622
[7]   Phosphoinositide 3-kinase regulates crosstalk between Trk A tyrosine kinase and p75NTR-dependent sphingolipid signaling pathways [J].
Bilderback, TR ;
Gazula, VR ;
Dobrowsky, RT .
JOURNAL OF NEUROCHEMISTRY, 2001, 76 (05) :1540-1551
[8]   Nerve growth factor-induced p75-mediated death of cultured hippocampal neurons is age-dependent and transduced through ceramide generated by neutral sphingomyelinase [J].
Brann, AB ;
Tcherpakov, M ;
Williams, IM ;
Futerman, AH ;
Fainzilber, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (12) :9812-9818
[9]  
Brann AB, 1999, J NEUROSCI, V19, P8199
[10]   p75(NTR) and apoptosis: Trk-dependent and Trk-independent effects [J].
Bredesen, DE ;
Rabizadeh, S .
TRENDS IN NEUROSCIENCES, 1997, 20 (07) :287-290