The transmembrane domain of the p75 neurotrophin receptor stimulates phosphorylation of the TrkB tyrosine kinase receptor

Abstract

The function of protein products generated from intramembraneous cleavage by the γ-secretase complex is not well defined. The γ-secretase complex is responsible for the cleavage of several transmembrane proteins, most notably the amyloid precursor protein that results in Aβ, a transmembrane (TM) peptide. Another protein that undergoes very similar γ-secretase cleavage is the p75 neurotrophin receptor. However, the fate of the cleaved p75 TM domain is unknown. p75 neurotrophin receptor is highly expressed during early neuronal development and regulates survival and process formation of neurons. Here, we report that the p75 TM can stimulate the phosphorylation of TrkB (tyrosine kinase receptor B). phosphorylation experiments indicated that a peptide representing p75 TM increases TrkB phosphorylation in a dose- and time-dependent manner. Moreover, mutagenesis analyses revealed that a valine residue at position 264 in the rat p75 neurotrophin receptor is necessary for the ability of p75 TM to induce TrkB phosphorylation. Because this residue is just before the γ-secretase cleavage site, we then investigated whether the p75(αγ) peptide, which is a product of both α- and γ-cleavage events, could also induce TrkB phosphorylation. Experiments using TM domains from other receptors, EGFR and FGFR1, failed to stimulate TrkB phosphorylation. Co-immunoprecipitation and biochemical fractionation data suggested that p75 TM stimulates TrkB phosphorylation at the cell membrane. Altogether, our results suggest that TrkB activation by p75(αγ) peptide may be enhanced in situations where the levels of the p75 receptor are increased, such as during brain injury, Alzheimer's disease, and epilepsy.

Excessive Treadmill Training Enhances Brain-Specific MicroRNA-34a in the Mouse Hippocampus

“…Similarly, our study also showed these changes. Moreover, the transmembrane domain of the p75 stimulates phosphorylation of the TrkB during brain injury, Alzheimer's disease, and epilepsy (Saadipour et al, 2017). Elevated p75 protein/TrkB phosphorylation levels were also found in OT groups in our study, which likely indicated maladaptation.…”

proBDNF is modified by advanced glycation end products in Alzheimer’s disease and causes neuronal apoptosis by inducing p75 neurotrophin receptor processing

“…Moreover, amyloidogenesis is aggravated by the interaction of beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) with p75 upon the binding of Aβ to p75 [ 21 ]. In contrast, it was shown that the p75ECD has a neuroprotective effect against Aβ toxicity [ 61 ] and that transmembrane domain of p75, has trophic effects by inducing phosphorylation of TrKB [ 62 ]. Our results emphasize the important contribution of p75 signaling, including p75ICD internalization and apoptosis, in AD pathogenesis upon AGE-modified proBDNF stimulation.…”

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