A role for Fyn in Trk receptor transactivation by G-protein-coupled receptor signaling.
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.
Rajagopal
Rithwick
R
Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology and Physiology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Chao
Moses V
MV
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010627:Phenethylamines / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D016415:Sequence Alignment
D000959:Antihypertensive Agents; D007527:Isoenzymes; D010627:Phenethylamines; D043562:Receptors, G-Protein-Coupled; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D020917:Receptor, trkA; D020813:Receptor, trkB; D051076:Proto-Oncogene Proteins c-fyn; D010749:Phosphoprotein Phosphatases; D000241:Adenosine