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K‐252b Potentiation of Neurotrophin‐3 Is trkA Specific in Cells Lacking p75 NTR
Author(s) -
Maroney Anna C.,
Sanders Christa,
Neff Nicola T.,
Dionne Craig A.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68010088.x
Subject(s) - tropomyosin receptor kinase a , low affinity nerve growth factor receptor , neurotrophin , tropomyosin receptor kinase c , tropomyosin receptor kinase b , trk receptor , nerve growth factor , long term potentiation , neurotrophin 3 , biology , endocrinology , medicine , receptor , microbiology and biotechnology , brain derived neurotrophic factor , chemistry , neurotrophic factors , platelet derived growth factor receptor , biochemistry , growth factor
Abstract: K‐252b potentiates the neurotrophic effects of neurotrophin‐3 (NT‐3) in primary cultures of rat central cholinergic and peripheral sensory neurons and in a rat pheochromocytoma PC12 cell line. The ligand and receptor specificity, and role of the low‐affinity neurotrophin receptor (p75 NTR ) in the potentiation response induced by K‐252b, are unknown. To address the issues of ligand and receptor specificity of K‐252b potentiation, we have examined neurotrophin‐induced DNA synthesis ([ 3 H]thymidine incorporation) in NIH3T3 cells expressing trkA, trkB, or trkC . Neither NT‐3 nor K‐252b alone could stimulate mitogenic activity in the trkA ‐overexpressing clone. However, coaddition of K‐252b (EC 50 of ∼2 n M ) with 10–100 ng/ml NT‐3 led to incorporation of [ 3 H]thymidine in trkA expressing cells to a level induced by optimal concentrations of nerve growth factor (NGF). The K‐252b‐ and NT‐3‐induced [ 3 H]thymidine incorporation correlated with an increase in the tyrosine autophosphorylation of the trkA receptor as well as tyrosine phosphorylation of trk ‐associated phospholipase C‐γ1 and SH2‐containing proteins. K‐252b did not potentiate submaximal doses of NGF, or maximal doses of brain‐derived neurotrophic factor (BDNF) or neurotrophin‐4/5 (NT‐4/5) in trkA ‐expressing cells. Furthermore, K‐252b did not potentiate DNA synthesis by submaximal doses of BDNF, NT‐4/5, or NT‐3 in trkB ‐ or trkC ‐expressing NIH3T3 cells, suggesting that the potentiation profile for K‐252b was specific for NT‐3 in trkA ‐expressing cells. We found no expression of p75 NTR in the trk ‐expressing NIH3T3 cells. This is the first demonstration that K‐252b potentiates a trkA ‐mediated biological nonneuronal response by NT‐3 that occurs independent of p75 NTR and appears to be both ligand and receptor specific.