Detection of p75NTR Trimers: Implications for Receptor Stoichiometry and Activation

Abstract

The p75 neurotrophin receptor (p75 NTR ) is a multifunctional receptor that participates in many critical processes in the nervous system, ranging from apoptosis to synaptic plasticity and morphological events. It is a member of the tumor necrosis factor receptor (TNFR) superfamily, whose members undergo trimeric oligomerization. Interestingly, p75NTR interacts with dimeric ligands (i.e., proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75 NTR signaling are trimeric (i.e., TNFRassociated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization in vitro and in mice brain tissues using a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75 NTR is a trimer and that monomers and trimers coexist at the cell surface. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75 NTR activation in a growth cone retraction functional assay. However, monomers are capable of inducing acute morphological effects in neurons. We propose that p75 NTR activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75 NTR confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…Our study indicates that while the percentages of NGFR-positive cells were uniformly increased after short treatment with vemurafenib or trametinib, not all melanoma cell populations resistant to either of these drugs showed higher frequency of NGFR-positive cells than their drug-naïve counterparts. As NGFR can trigger signaling in the absence of ligand, act as a homodimer or interact with the large number of different partners [62,63], it can be a component of diverse and possibly opposing signaling pathways and contribute to phenotype switching in melanoma [64]. Therefore, different expression of both, NGFR and MITF in melanoma cells might be responsible for diverse outcomes at the level of phenotype.…”

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

“…The interaction between the transmembrane domain of TrkB and the TrkB receptor may help provide insight into how p75 TM increases TrkB phosphorylation. Because p75 TM and TrkB TM both have more than four common amino acid residues implicated in their dimerization, including a cysteine and three valines in self-associative motifs ( Table 1, blue), we propose that the self-associative motifs may play a role in TrkB activation (9,39).…”

“…The p75 receptor shares many common features with the tumor necrosis family of receptors, including extracellular cysteine repeats, a single transmembrane domain, and a cytoplasmic domain with a death domain motif (6). Although controversial, p75 can exist as a monomer, as a dimer (7,8), or in a trimeric form similar to other tumor necrosis family members (9).…”

Harnessing autophagy to overcome mitogen‐activated protein kinase kinase inhibitor‐induced resistance in metastatic melanoma

“…However, results also suggest that CD271 may have opposing effects on autophagy in unstressed cells, such as CD271 + cells from treatment‐naïve cell lines that appear to require autophagy for survival vs. CD271 + cells undergoing drug‐induced stress, where CD271 appears to reduce cytotoxic autophagy. The role of CD271 as a component of diverse and/or opposing signalling networks is supported by recent studies characterizing CD271 as a regulator of the ‘phenotype switch’, and seems increasing likely given the large number of CD271‐interacting partners, as well as the ability of CD271 to function as a homodimer, or to elicit signalling in the absence of ligand binding …”