P90 ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling

Ryan T. Strachan, John Allen, Douglas J. Sheffler, Bryan L. Roth

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The 5-hydroxytryptamine 2A (5-HT2A) 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-HT2A receptor and attenuates 5-HT2A 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-HT2A 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-HT2A 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-HT2A receptors are regulated in vivo, with potential implications for human diseases in which 5-HT2A or RTK activity is altered (e.g., neuropsychiatric and neurodevelopmental disorders).

Original languageEnglish (US)
Pages (from-to)2657-2671
Number of pages15
JournalBiochemistry
Volume49
Issue number12
DOIs
StatePublished - Mar 30 2010
Externally publishedYes

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90-kDa Ribosomal Protein S6 Kinases
G-Protein-Coupled Receptor Kinases
Serotonin Receptors
G-Protein-Coupled Receptors
Serotonin
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor Receptor
Purinergic P2Y Receptors
Receptor Cross-Talk
Platelet-Derived Growth Factor Receptors
Growth Factor Receptors
Chemical activation
Vascular Smooth Muscle
Protein-Tyrosine Kinases
Smooth Muscle Myocytes
ribosomal protein S6 kinase, 90kDa, polypeptide 3
Fibroblasts
Neurons

ASJC Scopus subject areas

  • Biochemistry

Cite this

P90 ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling. / Strachan, Ryan T.; Allen, John; Sheffler, Douglas J.; Roth, Bryan L.

In: Biochemistry, Vol. 49, No. 12, 30.03.2010, p. 2657-2671.

Research output: Contribution to journalArticle

Strachan, Ryan T. ; Allen, John ; Sheffler, Douglas J. ; Roth, Bryan L. / P90 ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling. In: Biochemistry. 2010 ; Vol. 49, No. 12. pp. 2657-2671.
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