Title: Phosphorylation of Serine 779 in Fibroblast Growth Factor Receptor 1 and 2 by Protein Kinase C epsilon Regulates Ras/Mitogen-activated Protein Kinase Signaling and Neuronal Differentiation
Authors: Lonic, A
Powell, JA
Kong, Y
Thomas, D
Holien, JK
Truong, N
Parker, MW
Guthridge, MA
Issue Year: 2013
Publisher AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Series JOURNAL OF BIOLOGICAL CHEMISTRY: 288(21): 14874-14885
Abstract The FGF receptors (FGFRs) control a multitude of cellular processes both during development and in the adult through the initiation of signaling cascades that regulate proliferation, survival, and differentiation. Although FGFR tyrosine phosphorylation and the recruitment of Src homology 2 domain proteins have been widely described, we have previously shown that FGFR is also phosphorylated on Ser(779) in response to ligand and binds the 14-3-3 family of phosphoserine/threonine-binding adaptor/scaffold proteins. However, whether this receptor phosphoserine mode of signaling is able to regulate specific signaling pathways and biological responses is unclear. Using PC12 pheochromocytoma cells and primary mouse bone marrow stromal cells as models for growth factor-regulated neuronal differentiation, we show that Ser(779) in the cytoplasmic domains of FGFR1 and FGFR2 is required for the sustained activation of Ras and ERK but not for other FGFR phosphotyrosine pathways. The regulation of Ras and ERK signaling by Ser(779) was critical not only for neuronal differentiation but also for cell survival under limiting growth factor concentrations. PKC epsilon can phosphorylate Ser(779) in vitro, whereas overexpression of PKC epsilon results in constitutive Ser(779) phosphorylation and enhanced PC12 cell differentiation. Furthermore, siRNA knockdown of PKC epsilon reduces both growth factor-induced Ser(779) phosphorylation and neuronal differentiation. Our findings show that in addition to FGFR tyrosine phosphorylation, the phosphorylation of a conserved serine residue, Ser(779), can quantitatively control Ras/MAPK signaling to promote specific cellular responses.
URI: https://publications.svi.edu.au/publications/1683
Other Identifiers 10.1074/jbc.M112.421669
Publication type Article
Grant ID GNT0565217; GNT1021645
Find it online http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663510/