Open AccessChimeric tumor necrosis factor-TrkA receptors reveal that ligand-dependent activation of the TrkA tyrosine kinase is sufficient for differentiation and survival of PC12 cells.
Author(s) -
Giorgio Rovelli,
Renu A. Heller,
Marco Canossa,
Eric M. Shooter
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.18.8717
Subject(s) - tropomyosin receptor kinase a , neurite , tyrosine kinase , microbiology and biotechnology , tropomyosin receptor kinase c , receptor tyrosine kinase , biology , receptor , low affinity nerve growth factor receptor , nerve growth factor , tumor necrosis factor alpha , ror1 , transfection , cancer research , signal transduction , platelet derived growth factor receptor , endocrinology , growth factor , biochemistry , gene , in vitro
To elucidate the function of the two nerve growth factor (NGF) receptors, p75NGFR and p140trk, chimeric molecules were constructed of tumor necrosis factor (TNF) and NGF receptors. Rat PC12 pheochromocytoma cells transiently transfected with TNF-p140trk chimeras, which contain the extracellular domain of TNF receptor and the transmembrane and cytoplasmic domains of p140trk, showed TNF-dependent neuronal differentiation and cell survival. The activity of TNF-p140trk chimeras was completely blocked by the tyrosine kinase inhibitor K252a, and TNF was unable to induce neurite elongation in PC12 cells transfected with a tyrosine kinase-defective chimeric receptor. The TNF-p75NGFR chimeras, which contain the cytoplasmic domain of p75NGFR, were nonfunctional. Our results suggest that p140trk may function as ligand-activated homodimers and that ligand-mediated activation of the cytoplasmic domain of p140trk alone is sufficient for inducing a neuronal phenotype.