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Suramin Induces Phosphorylation of the High‐Affinity Nerve Growth Factor Receptor in PC12 Cells and Dorsal Root Ganglion Neurons
Author(s) -
Gill Jagjit S.,
Connolly Denise C.,
McManus Michael J.,
Maihle Nita J.,
Windebank Anthony J.
Publication year - 1996
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.1471-4159.1996.66030963.x
Subject(s) - suramin , nerve growth factor , neurite , dorsal root ganglion , tyrosine phosphorylation , biology , growth factor , platelet derived growth factor receptor , tropomyosin receptor kinase a , endocrinology , medicine , microbiology and biotechnology , phosphorylation , receptor , biochemistry , neuroscience , sensory system , in vitro
Suramin is a polysulfonated naphthylurea with demonstrated antineoplastic activity. Toxicity includes adrenal insufficiency and peripheral neuropathy. Although the mechanism of antitumor activity is unknown, inhibition of binding of growth factors to their receptors has been suggested. Growth factors inhibited by suramin include platelet‐derived growth factor, fibroblast growth factor, transforming growth factor, epidermal growth factor, insulin‐like growth factor, and nerve growth factor (NGF). In these studies, suramin was shown to be cytotoxic to PC12 cells in a dose‐dependent manner. At lower doses and in surviving cells, we observed the induction of neurite outgrowth. To determine the mechanism of suramin‐induced neurite outgrowth, PC12 cells were exposed to suramin and/or NGF for various time periods and treated cells were analyzed, by western blot analysis, for expression of tyrosine phosphoproteins. There was a similarity in the pattern of tyrosine‐phosphorylated proteins in PC12 cells stimulated with suramin or NGF. Of particular interest was the rapid phosphorylation (by 1 min) of the high‐affinity NGF (TrkA) receptor. Activation of other members of the signal‐transduction cascade (Shc, p21 ras , Raf‐1, ERK‐1) revealed similar phosphorylation levels induced by suramin and NGF. Parallel studies were performed in rat dorsal root ganglion cultures; suramin potentiated neurite outgrowth and activated the NGF receptor on these cells. This finding of specific patterns of tyrosine phosphorylation of cellular proteins in response to suramin treatment demonstrated that suramin is a partial agonist for the NGF receptor in both PC12 cells and dorsal root ganglion neurons.