Figure 1.

Signaling cascades mediated by Trk receptors and p75^NTR. Trk family members recruit and increase the phosphorylation of PLC-γ and Src homologous and collagen-like adaptor protein (Shc), which leads to activation of PI3K and Erk, and participate in cell survival, differentiation, and synaptic plasticity, respectively. Collaboration of p75^NTR with Trk augments the Trk effects. In the absence of Trk, p75^NTR predominantly signals to activate NF-κB and Jun N-terminal kinase (JNK), and modulates RhoA activity. Pro-neurotrophins also preferentially bind to the p75^NTR signaling apoptotic pathways. These responses are mediated through adaptor proteins that bind to the cytoplasmic domain of p75, including neurotrophin-receptor interacting factor (NRIF), neurotrophin-associated cell death executor (NADE), neurotrophin-receptor-interacting MAGE homolog (NRAGE), and Schwann cell 1 (SC1), which can exert effects on apoptosis, growth cone collapse and cell cycle arrest. Akt, protein kinase B; FRS2, fibroblast growth factor receptor substrate 2; Gab1, Grb2-associated binder-1; Grb2, growth factor receptor-bound protein 2; MEK, mitogen-activated protein kinase (MAPK)/Erk kinase; SOS, Son of Sevenless; TRAF6, tumor necrosis factor receptor-associated factor 6.