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Transactivation of PDGFRbeta by dopamine D4 receptor does not require PDGFRbeta dimerization
Sum Shing Chi1, Sandra M Vetiska, Robin S Gill
1Department of Neuroscience, Centre for Addiction and Mental Health, University of Toronto, Toronto M5T 1R8, Canada.
Molecular Brain
|July 28, 2010
Summary
G protein-coupled receptors (GPCRs) can activate receptor tyrosine kinases (RTKs) independently of ligands. Dopamine receptor D4 (DRD4) activates PDGFRbeta signaling without PDGFRbeta dimerization or phosphorylation, revealing a novel transactivation pathway.
Area of Science:
- Cellular signaling
- Molecular biology
- Biochemistry
Background:
- Receptor tyrosine kinases (RTKs) mediate signal transduction through dimerization and cross-phosphorylation.
- G protein-coupled receptors (GPCRs) can activate RTKs via transactivation.
- The established model involves ligand-induced RTK dimerization and phosphorylation.
Purpose of the Study:
- To investigate the mechanism of platelet-derived growth factor receptor beta (PDGFRbeta) transactivation by dopamine receptor D4 (DRD4).
- To determine if PDGFRbeta transactivation by DRD4 requires PDGFRbeta ligands, dimerization, or phosphorylation.
- To elucidate a novel GPCR-RTK signaling pathway.
Main Methods:
- Investigated PDGFRbeta transactivation by DRD4 in cellular models.
- Utilized pharmacological inhibitors to block PDGFRbeta dimerization and phosphorylation.
- Assessed downstream signaling to ERK1/2.
Main Results:
- DRD4-mediated PDGFRbeta transactivation occurs independently of PDGFRbeta ligands.
- PDGFRbeta maintains signaling capacity even when dimerization and phosphorylation are inhibited.
- The DRD4-PDGFRbeta-ERK1/2 pathway functions without canonical RTK activation steps.
Conclusions:
- GPCRs can transactivate RTKs through mechanisms distinct from ligand-induced dimerization and phosphorylation.
- The DRD4-PDGFRbeta pathway represents a novel mode of RTK transactivation.
- This finding expands our understanding of cross-talk between GPCRs and RTKs in cellular signaling.
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