Signal Transduction Pathways of G Protein-coupled Receptors and Their Cross-Talk with Receptor Tyrosine Kinases: Lessons from Bradykinin Signaling

Claus      Liebmann; Frank   D.   Bohmer

doi:10.2174/0929867003374589

Abstract

G protein-coupled receptors (GPCRs) represent a major class of drug targets. Recent investigation of GPCR signaling has revealed interesting novel features of their signal transduction pathways which may be of great relevance to drug application and the development of novel drugs. Firstly, a single class of GPCRs such as the bradykinin type 2 receptor (B2R) may couple to different classes of G proteins in a cell-specific and time-dependent manner, resulting in simultaneous or consecutive initiation of different signaling chains. Secondly, the different signaling pathways emanating from one or several GPCRs exhibit extensive cross-talk, resulting in positive or negative signal modulation. Thirdly, GPCRs including B2R have the capacity for generation of mitogenic signals. GPCR-induced mitogenic signaling involves activation of the p44 p42 mitogen activated protein kinases (MAPK) and frequently transactivation of receptor tyrosine kinases (RTKs), an unrelated class of receptors for mitogenic polypeptides, via currently only partly understood pathways. Cytoplasmic tyrosine kinases and protein-tyrosine phosphatases (PTPs) which regulate RTK signaling are likely mediators of RTK transactivation in response to GPCRs. Finally, GPCR signaling is the subject of regulation by RTKs and other tyrosine kinases, including tyrosine phosphorylation of GPCRs itself, of G proteins, and of downstream molecules such as members of the protein kinase C family. In conclusion, known agonists of GPCRs are likely to have unexpected effects on RTK pathways and activators of signal-mediating enzymes previously thought to be exclusively linked to RTK activity such as tyrosine kinases or PTPs may be of much interest for modulating GPCR-mediated biological responses.

Keywords: kwd, >, signal transduction, G protein coupled receptors, tyrosine kinases, GPCRs, bradykinin type 2 receptors B2R, mitogen activated protein kinases, RTK, glycosylation, palmitoylation, phosphorylation, heterotrimer G proteins, signal mediators, adynylate cyclase isoform II A, phospholipase, phospholipases, lipidkinases, phospholipid derived, bradykinin B2 receptors medaitated signal transduction, receptors tyrosine kinases RTK, MAP Kinases, RTK induced tyrosine phosphorylatin