Genetic dissection of neurotrophin signaling through the p75 neurotrophin receptor

Cell Rep. 2012 Dec 27;2(6):1563-70. doi: 10.1016/j.celrep.2012.11.009. Epub 2012 Dec 20.

Abstract

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 important for regulation of cell death, NF-κB, 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-κB 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NIH 3T3 Cells
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Protein Structure, Tertiary
  • Rats
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Receptors, Growth Factor
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / genetics
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • ARHGDIA protein, human
  • NF-kappa B
  • NGFR protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Receptors, Growth Factor
  • Receptors, Nerve Growth Factor
  • TNFRSF16 protein, mouse
  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • RHOA protein, human
  • Ngfr protein, rat
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse
  • MAP Kinase Kinase 4
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein