Identification of the Cytoplasmic Regions of Fibroblast Growth Factor (FGF) Receptor 1 Which Play Important Roles in Induction of Neurite Outgrowth in PC12 Cells by FGF-1

Lin, Hsiang Yin; Xu, Jingsong; Ischenko, Irene; Ornitz, David M.; Halegoua, Simon; Hayman, Michael J.

doi:10.1128/mcb.18.7.3762

Cited by 62 publications

(40 citation statements)

References 54 publications

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“…Nevertheless, ERK activity does appear to be required for FGF-2-induced differentiation since an inhibitor of ERK activation blocks neurite outgrowth by 90%. This result is consistent with previous studies on FGF-2 signaling in PC12 cells (60,62), but not with a recent study on FGF-2 signaling in a conditionally immortalized rat hippocampal cell line (63). However, this difference may be a reflection of the fact that these two cell lines are models for different types of neurons, which, therefore, may show distinct, cell type-specific responses to FGF-2 treatment.…”

Section: Discussionsupporting

confidence: 81%

p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation

Maher

1999

Journal of Biological Chemistry

134

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Basic fibroblast growth factor (FGF-2) is a member of a family of polypeptides that have roles in a wide range of biological processes. To determine why different cell types show distinct responses to treatment with FGF-2, the array of FGF receptors present on the surface of a cell which differentiates in response to FGF-2 (PC12 cells) was compared with that present on the surface of a cell that proliferates in response to FGF-2 (Swiss 3T3 fibroblasts). Both cell types express exclusively FGFR1, suggesting that there are cell type-specific FGFR1 signaling pathways. Since mitogen-activated protein kinases function as mediators of cellular responses to a variety of stimuli, the roles of these proteins in FGFmediated responses were examined. FGF-2 activates extracellular signal-regulated kinases with similar kinetics in both fibroblasts and PC12 cells, and a specific inhibitor of extracellular signal-regulated kinase activation blocks differentiation but has little effect on proliferation. In contrast, while p38 mitogen-activated protein kinase is activated weakly and transiently in PC12 cells treated with FGF-2, a much stronger and sustained activation of this kinase is seen in FGF-2-treated fibroblasts. Furthermore, specific inhibitors of this kinase block proliferation but have no effect on differentiation. This effect on proliferation is specific for FGF-2 since the same concentrations of inhibitors have little or no effect on proliferation induced by serum.Basic and acidic fibroblast growth factors 1 are the prototypes for a large family of multifunctional growth factors, which have been identified in a wide variety of tissues (for reviews see Refs. 1-4). Although FGFs were first characterized on the basis of their ability to stimulate cell proliferation, it is now known that FGFs can modulate a number of other cellular functions, including promotion or inhibition of differentiation, survival, protease synthesis and secretion, and chemotaxis. However, the pathways that mediate these cell type-specific effects of FGFs are not well understood.The FGFs interact with two classes of FGF receptors: high affinity receptors, which bind FGFs with picomolar affinity and are thought to mediate the cellular responses to FGF; and low affinity receptors, which bind FGFs with nanomolar affinity and are characterized by the presence of heparan sulfate moieties. The family of high affinity FGF receptors contains four closely related members (for reviews, see Refs. 4 -7), which all possess intrinsic tyrosine kinase activity. In addition, a number of alternately spliced mRNAs corresponding to multiple isoforms of FGF receptor-1 (FGFR1), FGF receptor-2 (FGFR2), and FGF receptor-3 (FGFR3) (8 -11) have been identified. These isoforms include receptors lacking Ig-like domain I (two Ig-like domain isoform) and/or alternative sequences for the second half of Ig-like domain III (receptor isoforms a, b, and c). In a recent study, the interaction of nine members of the FGF family with the four FGF receptors was examined using the induct...

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Section: Discussionsupporting

confidence: 81%

p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation

Maher

1999

Journal of Biological Chemistry

134

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“…For example, only FGFR1 stimulated phosphorylation of an 80 kD protein in L6 cells (Wang et al, 1994), while only FGFR4 was shown to be able to co-immunoprecipitate an 85 kD serine/threonine kinase (Vainikka et al, 1994(Vainikka et al, , 1996. Moreover, FGFR1 was shown to be much more potent than FGFR3 in inducing neurite outgrowth of PC12 cells (Lin et al, 1996), and this activity was localized to the juxtamembrane region of FGFR1, which mediated sustained phosphorylation of FRS2 and MAPK (Lin et al, 1998). Results presented here are consistent with the idea that FGFR1 is the most potent member of the FGFR family in mediating mitogenic signals.…”

Section: Other Comparative Studies Involving Fgfrsmentioning

confidence: 99%

Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4

et al. 2000

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The ®broblast growth factor receptor (FGFR) family members mediate a number of important cellular processes, and are mutated or overexpressed in several forms of human cancer. Mutation of Lys650?Glu in the activation loop of the FGFR3 kinase domain causes the lethal human skeletal disorder thanatophoric dysplasia type II (TDII) and is also found in patients with multiple myeloma, bladder and cervical carcinomas. This mutation leads to constitutive activation of FGFR3. To compare the signaling activity of FGFR family members, this activating mutation was generated in FGFR1, FGFR3, and FGFR4. We show that the kinase domains of FGFR1, FGFR3, and FGFR4 containing the activation loop mutation, when targeted to the plasma membrane by a myristylation signal, can transform NIH3T3 cells and induce neurite outgrowth in PC12 cells. Phosphorylation of Shp2, PLC-g, and MAPK was also stimulated by all three`TDII-like' FGFR derivatives. Additionally, activation of Stat1 and Stat3 was observed in cells expressing the activated FGFR derivatives. Finally, we demonstrate that FGFR1, FGFR3, and FGFR4 derivatives can stimulate PI-3 kinase activity. Our comparison of these activated receptor derivatives reveals a signi®cant overlap in the panel of eector proteins used to mediate downstream signals. This also represents the ®rst demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellular transformation. Moreover, our results suggest that Stat activation by FGFRs is important in their ability to act as oncogenes. Oncogene (2000) 19, 3309 ± 3320.

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“…For instance, the expression of different FGFR types is regulated during oligodendrocyte maturation, providing a molecular basis for the developmentally varying response of cells to a common ligand (16). Specificity can also originate from the type of receptor expressed, because all of the FGFRs do not appear to have the same efficiency at activating various downstream pathways (17)(18)(19). In addition, the location of the receptor or downstream events within the cell may add another level of specificity in the signaling response.…”

mentioning

confidence: 99%

Fibroblast Growth Factor-2-induced Signaling through Lipid Raft-associated Fibroblast Growth Factor Receptor Substrate 2 (FRS2)

Ridyard¹,

Robbins

2003

Journal of Biological Chemistry

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The plasma membrane is not homogenous but contains specific subcompartments characterized by their unique lipid and protein composition. Based on their enrichment in various signaling molecules, these membrane microdomains are recognized to be sites of localized signal transduction for a number of extracellular stimuli. We have previously shown that fibroblast growth factor-2 (FGF2) induced a specific signaling response within a lipid raft membrane microdomain in human neuroblastoma cells characterized by the tyrosine phosphorylation of a p80 phosphoprotein. Herein, we show that this protein is the signaling adaptor FRS2 and that it is localized exclusively to lipid rafts in vitro and in vivo. We have examined how the tyrosine phosphorylation and serine-threonine phosphorylation of FRS2 within lipid rafts affect the response of cells to FGF2 signaling. Our data suggest that activation of protein kinase C, Src family kinases, and MEK1/2 are involved in regulating serine-threonine phosphorylation of FRS2, which can indirectly affect FRS2 phosphotyrosine levels. We also show that Grb2 is recruited to lipid rafts during signaling events and that activation of MEK1/2 by different mechanisms within lipid rafts may lead to different cellular responses. This work suggests that compartmentalized signaling within lipid rafts may provide a level of specificity for growth factor signaling.

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Identification of the Cytoplasmic Regions of Fibroblast Growth Factor (FGF) Receptor 1 Which Play Important Roles in Induction of Neurite Outgrowth in PC12 Cells by FGF-1

Cited by 62 publications

References 54 publications

p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation

p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation

Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4

Fibroblast Growth Factor-2-induced Signaling through Lipid Raft-associated Fibroblast Growth Factor Receptor Substrate 2 (FRS2)

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