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.
Highlights
The FGF receptors (FGFRs) regulate pleiotropic cellular responses
We show that growth factor stimulation of either PC12 cells or bone marrow stromal cells (BMSCs) triggers the phosphorylation of Ser779 in the cytoplasmic tail of FGFR1 and FGFR2, which is essential for sustained ERK signaling together with neurite outgrowth and differentiation
The ability of growth factor receptor tyrosine phosphorylation to control diverse cellular responses represents a central paradigm in cell biology, the functional roles of receptor serine phosphorylation are less well understood
Summary
The FGF receptors (FGFRs) regulate pleiotropic (diverse) cellular responses. Results: Serine 779 phosphorylation of FGFR1 and 2 by PKC⑀ promotes maximal Ras/MAPK signaling and neuronal differentiation. Whether Ser779, which is conserved between FGFR1 and FGFR2, is important for regulating specific intracellular signaling pathways or biological responses such as differentiation has remained unclear In these studies, we sought to examine the potential roles of Ser779 signaling in mediating the ability of the FGFs to promote the neuronal differentiation of PC12 cells and primary mouse bone marrow stromal cells (BMSCs). We further demonstrate that the novel PKC (nPKC) isoform, PKC⑀, is responsible for Ser779 phosphorylation leading to Ras and ERK activation and neuronal differentiation These findings demonstrate that, in addition to phosphotyrosine residues in the cytoplasmic tails of FGFR1 and FGFR2, the phosphorylation of Ser779 can initiate intracellular signaling to control specific cellular responses such as neuronal differentiation
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