Crosstalk between p38 and Erk 1/2 in Downregulation of FGF1-Induced Signaling.

Published on Apr 12, 2019in International Journal of Molecular Sciences4.556
· DOI :10.3390/IJMS20081826
Malgorzata Zakrzewska17
Estimated H-index: 17
(UWr: University of Wrocław),
Lukasz Opalinski3
Estimated H-index: 3
(UWr: University of Wrocław)
+ 2 AuthorsAntoni Wiedlocha12
Estimated H-index: 12
(University of Oslo)
Sources
Abstract
Mitogen-activated protein kinases (MAPK): Erk1 and Erk2 are key players in negative-feedback regulation of fibroblast growth factor (FGF) signaling. Upon activation, Erk1 and Erk2 directly phosphorylate FGF receptor 1 (FGFR1) at a specific serine residue in the C-terminal part of the receptor, substantially reducing the tyrosine phosphorylation in the receptor kinase domain and its signaling. Similarly, active Erks can also phosphorylate multiple threonine residues in the docking protein FGF receptor substrate 2 (FRS2), a major mediator of FGFR signaling. Here, we demonstrate that in NIH3T3 mouse fibroblasts and human osteosarcoma U2OS cells stably expressing FGFR1, in addition to Erk1 and Erk2, p38 kinase is able to phosphorylate FRS2. Simultaneous inhibition of Erk1/2 and p38 kinase led to a significant change in the phosphorylation pattern of FRS2 that in turn resulted in prolonged tyrosine phosphorylation of FGFR1 and FRS2 and in sustained signaling, as compared to the selective inhibition of Erks. Furthermore, excessive activation of p38 with anisomycin partially compensated the lack of Erks activity. These experiments reveal a novel crosstalk between p38 and Erk1/2 in downregulation of FGF-induced signaling.
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