Abstract
The crosstalk between the P2Y(2) G-protein-coupled receptor (GPCR) with TrkA receptor tyrosine kinase (RTK) is an important mechanism that regulates neuronal differentiation. We show that Src family kinases (SFK) regulate P2Y(2)-TrkA molecular crosstalk. SFK inhibitors block ATPgammaS/P2Y(2)-promoted enhancement of NGF/TrkA signaling and neuronal differentiation in PC12 cells, abrogate the enhancement by ATPgammaS of neurite outgrowth in primary cultures of dorsal root ganglion neurons, and block co-immunoprecipitation of TrkA, P2Y(2) receptors and SFK. These results identify SFK as mediating nucleotide-enhanced neurotrophin-dependent neuronal differentiation and thus, as a key convergence point for interaction between RTKs and GPCRs.
MeSH terms
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / pharmacology
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Animals
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Cell Differentiation* / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Enzyme Activation / drug effects
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Immunoprecipitation
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Mice
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Mice, Inbred C57BL
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Nerve Growth Factor / pharmacology
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Neurons / cytology*
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Neurons / metabolism*
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Protein Binding
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Protein Kinase Inhibitors / pharmacology
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RNA, Small Interfering / genetics
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Rats
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Receptor, trkA / metabolism*
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Receptors, Purinergic P2 / genetics
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Receptors, Purinergic P2 / metabolism*
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Receptors, Purinergic P2Y2
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Signal Transduction / drug effects
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / metabolism*
Substances
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P2ry2 protein, mouse
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Receptors, Purinergic P2
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Receptors, Purinergic P2Y2
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adenosine 5'-O-(3-thiotriphosphate)
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Adenosine Triphosphate
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Nerve Growth Factor
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Receptor, trkA
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src-Family Kinases