RET receptor expression and interaction with TRK receptors in neuroblastomas

Abstract

Neuroblastomas (NBs) have heterogeneous clinical behavior, from spontaneous regression or differentiation to relentless progression. Evidence from our laboratory and others suggests that neurotrophin receptors contribute to these disparate behaviors. Previously, the role of TRK receptors in NB pathogenesis was investigated. In the present study, the expression of RET and its co-receptors in a panel of NB cell lines was investigated and responses to cognate ligands GDNF, NRTN, and ARTN with GFRα1-3 co-receptor expression, respectively were found to be correlated. RET expression was high in NBLS, moderate in SY5Y, low/absent in NBEBc1 and NLF cells. All cell lines expressed at least one of GFRα co-receptors. In addition, NBLS, SY5Y, NBEBc1 and NLF cells showed different morphological changes in response to ligands. As expected, activation of RET/GFRα3 by ARTN resulted in RET phosphorylation. Interestingly, activation of TrkA by its cognate ligand NGF resulted in RET phosphorylation at Y905, Y1015, and Y1062, and this was inhibited in a dose-dependent manner by the TRK inhibitor (CEP-701). Conversely, RET activation by ARTN in NBLS cells led to phosphorylation of TrkA. This suggests a physical association between RET and TRK proteins, and cross-talk between these two receptor pathways. Finally, RET, GFR and TRK expression in primary tumors was investigated and a significant association between RET, its co-receptors and TRK expression was demonstrated. Thus, the present data support a complex model of interacting neurotrophin receptor pathways in the regulation of cell growth and differentiation in NBs.

Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology

“…Therefore, a cell-type specific GFRα2/GFRα3 ratio could indeed determine the tumor promoting vs. tumor suppressing behavior of RET. This hypothesis is further supported by expression correlation data across 12 publicly available neuroblastoma datasets [75], which showed significantly positive associations of RET with GFRA2, but negative in the case of GFRA3. Other signaling components could also contribute to this decision.…”

Revisiting Neuroblastoma: Nrf2, NF-κB and Phox2B as a Promising Network in Neuroblastoma

“…This transcription factor also controls the transcription of RET, another RTK such as PI3K. RET is indispensable for physiologic development of sympathetic neurons [103] and its inactivating mutations and polymorphisms are a major cause of Hirschsprung's disease, defined by colonic aganglionosis [104]. In addition, RET interacts with ALK and TRK, likewise members of the RTK family [103].…”

“…RET is indispensable for physiologic development of sympathetic neurons [103] and its inactivating mutations and polymorphisms are a major cause of Hirschsprung's disease, defined by colonic aganglionosis [104]. In addition, RET interacts with ALK and TRK, likewise members of the RTK family [103]. Recently it has been more precisely defined that RET hyperactivation is driven by ALK in neuroblastoma [95].…”

Neural crest cells development and neuroblastoma progression: Role of Wnt signaling

“…TrkA (encoded by NTRK1), TrkB (encoded by NTRK2) and TrkC (encoded by NTRK3) are neurotrophic receptors that have been reported to have a crucial role in NB pathogenesis (Thomaz et al, 2020). TrkA and TrkC overexpression have been associated with spontaneous regression with better clinical and biological outcomes in NB patients (Tetri et al, 2020). NB in the early stages expresses significantly lower levels of NGF, elevated levels of TrkA and quite the opposite in advanced stages of NB, suggesting NGF/ TrkA pathway plays an essential role in NB regression (Pastor & Mousa, 2019).…”