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. 2021 May 26;22(11):5692. doi: 10.3390/ijms22115692

Figure 1.

Figure 1

Signaling pathways mediated by neurotrophins’ binding to their receptors. Neurotrophins bind to two main receptor types: Trk receptors and p75NTR. Pro-neurotrophins (proNT) processing generates mature neurotrophins (mNT). Upon mNT stimulation, Trk receptors undergo autophosphorylation events, and recruit adaptor proteins responsible for the activation of MAPKs, PI3K and PLCγ signaling cascades, involved in several neuronal functions such as neurite outgrowth. mNT may also bind to p75NTR, stimulating its proteolysis which releases the intracellular domain (p75ICD) that is essential for signalling and for the regulation of gene transcription. p75NTR activation by mNT may promote neuronal survival by inducing NF-kB signaling. In addition, Necdin recruitment to p75NTR may regulate cell cycle progression and differentiation in a variety of cell types, whereas the interaction with PDE4 and PKA is involved in the regulation of energy balance. Importantly, in dependence on the cell context, p75NTR activation by mNT is able to potentiate the activation of Trk receptors. On the other hand, the binding of proNT to the p75NTR/Sortilin complex enhances the activation of cell-death-related pathways. When p75NTR interacts with NOGO/LINGO1, the recruitment of Rho GDI leads to the activation of RhoA, which in turn determines the inhibition of neurite outgrowth in neurons. FAP1, FAS-associated phosphatase 1; GAB1, GRB2 Associated Binding Protein 1; Grb2, growth factor receptor-bound protein 2; IRS 1/2, insulin receptor substrate 1/2; JNK, c-Jun N-terminal kinases; LINGO1, leucine-rich repeat and Immunoglobin-like domain-containing protein 1; NADE, p75NTR-associated cell death executor; p75NTR, p75 neurotrophin receptor; NRAGE, neurotrophin receptor-interacting MAGE homologue; NRIF, neurotrophin receptor-interacting factor; PDE4, phosphodiesterase 4; PDK, phosphoinositide-dependent kinase; PKA, protein kinase A; PLCγ phospholipase Cγ; RhoA, Ras homolog family member A; RIP2, receptor-interacting protein 2; Shc, SRC homology domain-containing protein; SOS, son of sevenless; TRAF6, TNF receptor-associated factor 6; Trk, tropomyosin receptor kinase. This figure is created with BioRender.