The FGFR1 Inhibitor PD 173074 Selectively and Potently Antagonizes FGF‐2 Neurotrophic and Neurotropic Effects

Abstract

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 ϩ 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.

Dimeric Versions of Two Short N-cadherin Binding Motifs (HAVDI and INPISG) Function as N-cadherin Agonists

“…We have shown that a highly specific FGFR antagonist (PD17304) inhibits the agonist peptide responses. It is perhaps worth noting that, at the concentration used, this inhibitor fully blocks the response stimulated by FGF2 and native Ncadherin (15) in the absence of any effect on the insulin-like growth factor, platelet-derived growth factor, nerve growth factor, BDNF, CNTF, GDNF, and epidermal growth factor receptors (32,33). The possibility that the agonist peptides act directly at the level of the FGFR can be discounted, as the response to FGF2 is not inhibited by several of the agents that inhibit the peptide response (e.g.…”

“…Under the same conditions, this antibody inhibits the response to native N-cadherin in the absence of any effect on the neurite outgrowth response stimulated by FGF2, NCAM, and L1 (15). The conclusion that N-cadherin-dependent neurite outgrowth requires FGFR function in neurons has recently been further substantiated by showing that a highly specific antagonist of the FGFR (PD17304) (32,33) can inhibit the neurite outgrowth response stimulated by FGF2 and native N-cadherin with similar efficacy (15). This reagent also fully inhibited the response stimulated by the cyclic dimeric HAVDI and INPISG agonist peptides (Fig.…”

“…A monovalent F(abЈ) fraction of the whole antiserum was also prepared by standard methods, purified by HPLC, and stored as a stock at 33 mg/ml at 4°C. The FGFR antagonist PD17304 (32) was synthesized as previously described (33,34).…”

Tricyclic Antidepressant Amitriptyline-induced Glial Cell Line-derived Neurotrophic Factor Production Involves Pertussis Toxin-sensitive Gαi/o Activation in Astroglial Cells

“…The concentrations of inhibitors were used as described previously (30,31,38,39). GM6001, SU5402, PD173074 (1 M; FGFR inhibitor), and U0126 (10 M; MEK inhibitor) had no effect on the amitriptyline-induced increase in ⌬Z (Fig.…”

Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074

“…-yl]-urea, selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors 17 and was obtained from Pfizer Global Research and Development (Ann Arbor, MI). The compounds were dissolved in DMSO and stored at À201C.…”