G Protein-Coupled Receptor-Receptor Tyrosine Kinase Receptor Crosstalk: Regulation of Receptor Sensitivity and Roles of Autocrine Feedback Loops and Signal Integration

Receptor tyrosine kinases (RTKs) can induce G protein-coupled receptor (GPCR) desensitization and phosphorylation. In some cases phosphorylation by RTKs on GPCRs tyrosine residues is involved, while in others indirect action through diverse protein kinases takes place. GPCRs stimulation can lead to RTK activation through the action of metalloproteinases, shedding of HB-EGF, and EGF receptor activation; such autocrine loop participates in the overall action triggered by GPCRs. Interestingly, it also has a role in GPCR phosphorylation and desensitization induced by activation of unrelated agents acting through their own GPCRs, and even in homologous desensitization. Phosphorylation and desensitization of some GPCRs by RTKs is pertussis toxin-sensitive, suggesting a role of G proteins. This might involve interaction between G proteins and RTKs but also of another autocrine loop, which includes sphingosine kinase I activation, sphingosine 1-phosphate generation and release and sphingosine 1-phosphate GPCR stimulation. RTKs can also use GPCRs as accessory signalling elements placing G proteins downstream of RTKs. In this signal integration mechanism, synthesis/ release of GPCR agonists is not essential. Crosstalk between GPCRs and RTKs has both basic and clinical implications, and has roles in physiologic and pathologic conditions offering multiple sites for therapeutic intervention.