p90 Ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling.
The 5-hydroxytryptamine 2A (5-HT(2A)) receptor is a member of the G protein-coupled receptor superfamily (GPCR) and plays a key role in transducing a variety of cellular signals elicited by serotonin (5-HT; 5-hydroxytryptamine) in both peripheral and central tissues. Recently, we discovered that the ERK/MAPK effector p90 ribosomal S6 kinase 2 (RSK2) phosphorylates the 5-HT(2A) receptor and attenuates 5-HT(2A) receptor signaling. This raised the intriguing possibility of a regulatory paradigm whereby receptor tyrosine kinases (RTKs) attenuate GPCR signaling (i.e., "inhibitory cross-talk") by activating RSK2 [Strachan et al. (2009) J. Biol. Chem. 284, 5557-5573]. We report here that activation of multiple endogenous RTKs such as the epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor (PDGFR), and ErbB4 significantly attenuates 5-HT(2A) receptor signaling in a variety of cell types including mouse embryonic fibroblasts (MEFs), mouse vascular smooth muscle cells (mVSMCs), and primary cortical neurons. Importantly, genetic deletion of RSK2 completely prevented signal attenuation, thereby suggesting that RSK2 is a critical mediator of inhibitory cross-talk between RTKs and 5-HT(2A) receptors. We also discovered that P2Y purinergic receptor signaling was similarly attenuated following EGFR activation. By directly testing multiple endogenous growth factors/RTK pathways and multiple Gq-coupled GPCRs, we have now established a cellular mechanism whereby RTK signaling cascades act via RSK2 to attenuate GPCR signaling. Given the pervasiveness of growth factor signaling, this novel regulatory mechanism has the potential to explain how 5-HT(2A) receptors are regulated in vivo, with potential implications for human diseases in which 5-HT(2A) or RTK activity is altered (e.g., neuropsychiatric and neurodevelopmental disorders).
Department of Biochemistry, Case Western Reserve University Medical School, Cleveland, Ohio 44106, USA.
Ryan T
RT
Strachan
John A
JA
Allen
Douglas J
DJ
Sheffler
Bryan L
BL
Roth
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D011990:Receptors, Transferrin / Q000276:immunology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D015703:Antigens, CD; C068126:CD71 antigen; D010982:Platelet-Derived Growth Factor; D044402:Receptor, Serotonin, 5-HT2A; D043562:Receptors, G-Protein-Coupled; D011990:Receptors, Transferrin; D012701:Serotonin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3