Abstract
Genetic studies have established the crucial roles of FGF signaling, FGF-induced gene expression and morphogenesis during embryogenesis. In this study, we showed that overexpressing a signaling adaptor protein, SH2B1beta, enhanced FGF1-induced neurite outgrowth in PC12 cells. SH2B1beta has previously been shown to promote nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF)-induced neurite outgrowth, in part, through prolonging NGF and GDNF-induced signaling. To delineate how SH2B1beta promotes FGF1-induced neurite outgrowth, we examined its role in FGF1-dependent signaling. Our data suggest that SH2B1beta enhances and prolongs FGF1-induced MEK-ERK1/2 and PI3K-AKT pathways. We also provided the first evidence that FGF1 induces the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at serine 727 [pSTAT3(S727)] in PC12 cells. SH2B1beta enhances this phosphorylation and the expression of the immediate early gene, Egr1. Through inhibitor assays, we have further shown that MEK-ERK1/2 is required for FGF1-induced neurite outgrowth, pSTAT3(S727) and Egr1 expression. Moreover, inhibiting Rho kinase, ROCK, enhances FGF1-induced neurite outgrowth through pSTAT3(S727)-independent manner. Taken together, our results demonstrate, for the first time, that SH2B1beta enhances FGF1-induced neurite outgrowth in PC12 cells mainly through MEK-ERK1/2-STAT3-Egr1 pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Butadienes / pharmacology
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Carrier Proteins / metabolism*
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Chromones / pharmacology
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Early Growth Response Protein 1 / metabolism*
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Fibroblast Growth Factor 1 / pharmacology*
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Green Fluorescent Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinases / metabolism*
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Morpholines / pharmacology
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Nerve Growth Factors / pharmacology
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Neurites / drug effects*
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Neurites / enzymology*
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Nitriles / pharmacology
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PC12 Cells
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Phosphorylation / drug effects
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Recombinant Fusion Proteins / metabolism
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STAT3 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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rho-Associated Kinases / antagonists & inhibitors
Substances
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Butadienes
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Carrier Proteins
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Chromones
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Early Growth Response Protein 1
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Egr1 protein, rat
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Intracellular Signaling Peptides and Proteins
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Morpholines
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Nerve Growth Factors
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Nitriles
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Recombinant Fusion Proteins
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SH2B1 protein, rat
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STAT3 Transcription Factor
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Stat3 protein, rat
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U 0126
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Fibroblast Growth Factor 1
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Green Fluorescent Proteins
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Proto-Oncogene Proteins c-akt
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rho-Associated Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1