The effect of P75 on Trk receptors in neuroblastomas

Abstract

Neuroblastomas (NBs) with favorable outcome usually express TrkA, whereas unfavorable NBs frequently express TrkB and its cognate ligand BDNF. P75 (p75LNTR, NGFR, TNFRSF16) binds NGF-related neurotrophins with low affinity and usually is co-expressed with Trk receptors in NBs. Here, we investigated the importance of p75 coexpression with Trk receptors in NBs. We transfected p75 into two Trk-null NB cell lines, SH-SY5Y and NLF that were also engineered to stably express TrkA or TrkB. Cell numbers were compared between single (Trk alone) and double (Trk+p75) transfectants, and proliferation was assessed by flow cytometry. P75 coexpression had little effect on cell growth in Trk NB cells in the absence of ligand, but it increased sensitivity and greatly enhanced the effect of cognate ligand. Exogenous NGF induced greater phosphorylation of TrkA and AKT. This was associated with increased cell number in TrkA/p75 cells compared to TrkA cells (p<0.01), which was due to increased proliferation in TrkA/p75 cells (p<0.05), followed by differentiation. Exogenous BDNF also increased cell number in TrkB/p75 compared to TrkB cells (p<0.01), due to an increase in proliferation, but without differentiation. Co-expression of p75 also increased specificity of Trk-expressing cells to ligand. NT3-induced phosphorylation of TrkA and AKT was reduced in TrkA/p75 cells. NT3-induced phosphorylation of TrkB (as well as AKT and MAPK) was also reduced with p75 coexpression. Our results suggest that p75 plays an important role in enhancing both the sensitivity of Trk receptors to low levels of ligand, as well as increasing the specificity of Trks to their cognate ligands. It also enhances ligand-induced differentiation in TrkA/p75 but not TrkB/p75 cells.

Mechanisms of neuroblastoma regression

“…95–99 The TrkA and TrkC receptors are also known as dependence receptors, as the absence of ligand activation will generate apoptotic signals. 100,101 Coexpression of the P75/NGFR receptor can increase the sensitivity and specificity of all three Trk receptors for their cognate ligands; 102,103 however, overexpression and activation of P75/NGFR in the absence of Trk expression can lead to apoptosis. 101,104 …”

Inflammation and activity augment brain-derived neurotrophic factor peripheral release

“…In neurons, BDNF binds to high affinity receptor TrkB and sometimes binds to TrkB/p75 complex to enhance growth and survival promoting signals (Ho et al, 2011). In this study we show that the protein levels of TrkB and p75 are increased.…”

“…In neurons, BDNF binding to TrkB supports neuronal growth, survival and differentiation. Coupling of TrkB and p75 enhances BDNF action in growth and survive (Ho et al, 2011). On the other hand, pro-BDNF binding to p75 and Sortilin leads to apoptosis (Teng et al, 2005).…”

Neuroblastoma: A Malignancy Due to Cell Differentiation Block

“…While TRKA-and TRKC-mediated signalling decreases neuroblastoma cell proliferation and aggressiveness, BDNF/TRKB signalling corresponds with poor outcome in neuroblastoma patients [reviewed in (Edsjö, Holmquist, and Påhlman, 2007)]. BDNF treatment of neuroblastoma cells transfected with a TRKB over-expressing construct does not induce differentiation (Ho et al, 2011), and BDNF stimulation of neuroblastoma cell lines expressing TRKB as a result of RA treatment does not affect proliferation, but increases survival and invasiveness (Matsumoto et al, 1995). In addition to these effects of TRKA and TRKB signalling, recent data also suggest a difference with respect to therapy resistance, invasiveness, angiogenesis, and possibly also genomic stability (Schramm et al, 2005).…”