Premium
The FGFR1 Inhibitor PD 173074 Selectively and Potently Antagonizes FGF‐2 Neurotrophic and Neurotropic Effects
Author(s) -
Skaper Stephen D.,
Kee Wai Jing,
Facci Laura,
Macdonald Gregor,
Doherty Patrick,
Walsh Frank S.
Publication year - 2000
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.1471-4159.2000.0751520.x
Subject(s) - neurotrophic factors , fibroblast growth factor , neurite , glial cell line derived neurotrophic factor , gdnf family of ligands , neurotrophin , microbiology and biotechnology , biology , nerve growth factor , fibroblast growth factor receptor 1 , dorsal root ganglion , endocrinology , neuroscience , medicine , receptor , biochemistry , in vitro , spinal cord
Basic fibroblast growth factor (FGF‐2) promotes survival and/or neurite outgrowth from a variety of neurons in cell culture and regenerative processes in vivo . FGFs exert their effects by activating cell surface receptor tyrosine kinases. FGF receptor (FGFR) inhibitors have not been characterized on neuronal cell behaviors to date. In the present study, we show that the FGFR1 inhibitor PD 173074 potently and selectively antagonized the neurotrophic and neurotropic actions of FGF‐2. Nanomolar concentrations of PD 173074 prevented FGF‐2, but not insulin‐like growth factor‐1, support of cerebellar granule neuron survival under conditions of serum/K + deprivation; another FGF‐2 inhibitor, SU 5402, was effective only at a 1,000‐fold greater concentration. Neither PD 173074 nor SU 5402, at 100 times their IC 50 values, interfered with the survival of dorsal root ganglion neurons promoted by nerve growth factor, ciliary neurotrophic factor, or glial cell line‐derived neurotrophic factor. PD 173074 and SU 5402 displayed 1,000‐fold differential IC 50 values for inhibition of FGF‐2‐stimulated neurite outgrowth in PC12 cells and in granule neurons, and FGF‐2‐induced mitogen‐activated protein kinase (p44/42) phosphorylation. The two inhibitors failed to disturb downstream signalling stimuli of FGF‐2. PD 173074 represents a valuable tool for dissecting the role of FGF‐2 in normal and pathological nervous system function without compromising the actions of other neurotrophic factors.