Distinction between differentiation, cell cycle, and apoptosis signals in PC12 cells by the nerve growth factor mutant ?9/13, which is selective for the p75 neurotrophin receptor

Separate Cyclic AMP Sensors for Neuritogenesis, Growth Arrest, and Survival of Neuroendocrine Cells

“…In fact, different structural analogs of NGF have been shown to differentially induce signaling, leading to either differentiation or trophism/cytoprotection through TrkA receptors (56,57). GPCR ligands that specifically modulate these cellular outcomes in a biased fashion (58) could, therefore, be of great therapeutic potential.…”

Individual and Combined Effects of TrkA and p75NTR Nerve Growth Factor Receptors

“…4, E-H, see arrowheads). In agreement with previous studies (3,17), stimulation of PC12 cells with the p75 NTR -selective mutant ⌬9/13 NGF failed to elicit neurite outgrowth, resulting in an indistinguishable appearance from untreated cells (Fig. 4, A-D and I-L).…”

“…One of the earliest markers of apoptosis is disruption of the plasma membrane, with externalization of phosphatidylserine to the outer leaflet of the membrane. Annexin V is a calcium-dependent binding protein that has a high affinity for phosphatidylserine that is often used to measure the extent of plasma membrane disruption during the early stages of apoptosis (17). Annexin V staining of PC12 and PTR cells, performed 8 h after cells were placed in serum-free medium, was reduced upon treatment of cells with either 2 nM NGF or PDGF and/or ⌬9/13 NGF, lending further support to pro-survival signaling through either TrkA or p75 NTR (data not shown).…”

“…Because the PC12 cell line for studying the effects of NGF does not normally express PDGF receptors (PDGFR), addition of PDGF to PTR cells allows selective activation of the PDGF/TrkA chimera and TrkA receptor-specific signaling programs but not the activation of endogenous TrkA (15,16). In addition, the p75 NTRselective NGF mutant, ⌬9/13 NGF, that lacks TrkA binding but retains normal binding to p75 NTR (3,17), allows specific activation of p75 NTR signaling pathways alone. In the present study, we compared the separate but simultaneous activation of TrkA and p75 NTR oligomers versus functional analysis of NGF high affinity receptor formation.…”

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

“…The mutations in the N-terminus of NGF were shown to be important for TrkA binding in several laboratories (Section 4.1.1). One noteable mutein was the ∆9/13 mutein that bound p75 but not TrkA (Woo et al, 1995), and helped distinguish between differentiation, cell cycle regulation, and apoptosis in PC12 cells (Hughes et al, 2001). Utilization of this ∆9/13 mutein also later indicated a unique role for the 'high affinity' binding complex of p75 and TrkA in PC12 cells (Lad, et al, 2003b).…”