Abstract
Signaling through Trk receptor tyrosine kinases can occur in the absence of neurotrophins through certain G-protein-coupled receptors (GPCRs). It has previously been suggested that GPCR-mediated Trk activation occurs on intracellular membranes and involves several second messengers, including Src family kinases and intracellular calcium. Here, we describe a novel role for the Src family kinase, Fyn, in regulating signaling events between GPCRs and Trk. We find that Fyn expression is sufficient to allow transactivation of Trk by adenosine and that Fyn and Trk are colocalized in a juxtanuclear membrane compartment. Adenosine activation of Fyn results in direct phosphorylation of Trk in vitro and follows a delayed time course that coincides with Trk activation. These results indicate that Fyn is activated by GPCR stimulation and is responsible for transactivation of Trk receptors on intracellular membranes.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine / analogs & derivatives
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Adenosine / metabolism
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Amino Acid Sequence
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Animals
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Antihypertensive Agents / metabolism
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Cell Line
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Enzyme Activation
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Hippocampus / cytology
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Humans
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Intracellular Membranes / metabolism
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Isoenzymes / metabolism
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Neurons / cytology
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Neurons / metabolism
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Phenethylamines / metabolism
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-fyn / genetics
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Proto-Oncogene Proteins c-fyn / metabolism*
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Rats
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Rats, Sprague-Dawley
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Receptor, trkA / genetics
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Receptor, trkA / metabolism*
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Receptor, trkB / genetics
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Receptor, trkB / metabolism*
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Receptors, G-Protein-Coupled / metabolism*
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Receptors, Purinergic P1 / metabolism
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Second Messenger Systems / physiology*
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Sequence Alignment
Substances
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Antihypertensive Agents
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Isoenzymes
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Phenethylamines
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Receptors, G-Protein-Coupled
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Receptors, Purinergic P1
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2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
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Receptor, trkA
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Receptor, trkB
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Proto-Oncogene Proteins c-fyn
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Phosphoprotein Phosphatases
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Adenosine