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.
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. PKCε can phosphorylate Ser(779) in vitro, whereas overexpression of PKCε results in constitutive Ser(779) phosphorylation and enhanced PC12 cell differentiation. Furthermore, siRNA knockdown of PKCε 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.
authors.affiliation: Cell Growth and Differentiation Laboratory, Division of Human Immunology, South Australian Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Ana
authors.initials: A
authors.lastname: Lonic
authors.forename: Jason A
authors.initials: JA
authors.lastname: Powell
authors.forename: Yang
authors.initials: Y
authors.lastname: Kong
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Holien
authors.forename: Nhan
authors.initials: N
authors.lastname: Truong
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Mark A
authors.initials: MA
authors.lastname: Guthridge
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000502:physiology; D010768:Phosphoserine / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000201:enzymology
chemical_list: D010768:Phosphoserine; C497256:Prkce protein, mouse; C497257:Prkce protein, rat; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; C496354:Fgfr2 protein, mouse; C496356:Fgfr2 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; C497255:PRKCE protein, human; D051744:Protein Kinase C-epsilon; D015689:Oncogene Protein p21(ras)
keywords: Differentiation; ERK; Fibroblast Growth Factor (FGF); Fibroblast Growth Factor Receptor (FGFR); Protein Kinase C (PKC); Serine Phosphorylation
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