Structural determinants underlying signaling specificity in the tumor necrosis factor receptor superfamily (TNFRSF) are poorly characterized, and it is unclear whether different signaling outputs can be genetically dissociated. The p75 neurotrophin receptor (p75 NTR ), also known as TNFRSF16, is a key regulator of trophic and injury responses in the nervous system. Here, we describe a genetic approach for dissecting p75 NTR signaling and deciphering its underlying logic. Structural determinants

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... important for regulation of cell death, NF-kB, and RhoA pathways were identified in the p75 NTR death domain (DD). Proapoptotic and prosurvival pathways mapped onto nonoverlapping epitopes, demonstrating that different signaling outputs can be genetically separated in p75 NTR . Dissociation of c-Jun kinase (JNK) and caspase-3 activities indicated that JNK is necessary but not sufficient for p75 NTR -mediated cell death. RIP2 recruitment and RhoGDI release were mechanistically linked, indicating that competition for DD binding underlies crosstalk between NF-kB and RhoA pathways in p75 NTR signaling. These results provide insights into the logic of p75 NTR signaling and pave the way for a genetic dissection of p75 NTR function and physiology.