Trends in Pharmacological Sciences
OpinionGPCR-jacking: from a new route in RTK signalling to a new concept in GPCR activation
Introduction
Signal transduction initiated by both G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) is mediated by specific kinase dependent cascades. Over the past ten years, it has become evident that GPCRs and RTKs, which activate a common set of signalling molecules, do not operate in an isolated fashion. It has been well established that growth-promoting activity of many GPCR ligands involves activation of RTKs and their downstream signalling cascades 1, 2, 3. These observations have led to the emergence of the ‘transactivation’ concept, which designates a phenomenon by which a given receptor is activated by a ligand of a heterologous receptor that possibly belongs to a different class of receptor with respect to the signal transduction mechanism. Transactivation now classically refers to the activation of RTKs by GPCR ligands, which is an important pathway that links GPCRs to the extracellular signal-regulated kinase (ERK) signalling cascade 1, 2, 3. Reciprocally, an increasing body of evidence has revealed an engagement of GPCR signalling molecules (e.g. heterotrimeric G proteins and arrestins) in signal transduction generated by various RTK subtypes 4, 5, 6, 7, 8, 9, which raises an important question: does the reverse also occur, i.e. can RTKs transactivate GPCRs? Here, we provide a rapid overview of recent data that reveals the importance of this novel transactivation mechanism, which places the GPCR downstream of the RTK in a variety of cellular responses, including cell migration and survival. We also discuss how GPCR transactivation, which has so far been identified for only a few GPCR-RTK pairs, might be a general mechanism that can specify the nature of signal transduction mediated by RTKs.
Section snippets
GPCRs transactivate RTKs: a classic signalling pathway
Since the initial discovery that several GPCR agonists are capable of transactivating the epidermal growth factor (EGF) receptor [10], this mechanism has been generalized to many other RTKs, such as receptors for neurotrophins, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), which elicit a variety of cellular effects, including proliferation, differentiation, migration and survival 1, 3. Two modes of RTK transactivation by GPCRs have so far been identified. In the
RTKs use some GPCR signalling molecules to transduce signals
An increasing body of evidence indicates that RTKs exert some of their effects by engagement of GPCR signalling molecules, including heterotrimeric G proteins and β-arrestins, which raises the possibility that RTKs can also act as ‘GPCR like’ receptors. The inhibition of RTK-mediated activation of various effectors by molecules that disrupt GPCR signalling [e.g. Pertussis toxin or the C-terminal domain of G protein-coupled receptor kinase 2 (GRK2), which sequesters Gβγ proteins] provided the
RTKs highjack GPCRs themselves: towards a new concept in GPCR activation
Recent advances provide compelling evidence that signal transduction mediated by several RTKs is mediated, at least in part, by transactivation of GPCR themselves, which reveals a bidirectional cross-communication between RTKs and GPCRs (Table 1). Again, two distinct mechanisms have been involved in this reciprocal transactivation process, depending on the nature of the GPCR-RTK partners. In some GPCR-RTK partnerships, GPCR transactivation results from synthesis and secretion of a cognate
Conclusion
How a given RTK can exert specific physiological effects not mediated by other RTKs is still an open question. GPCR transactivation, which might contribute to the specification of growth factor signalling and functions, certainly provides an element of response. However, GPCR transactivation by RTK ligands has so far only been established for a few GPCR-RTK pairs and needs to be generalized to other GPCR-RTK partnerships to validate the concept. In this context, whether GPCRs known to promote
Acknowledgements
N.D. was supported by a fellowship from the French Ministère de la Recherche et de la Technologie. J.B. is a recipient of grants from CNRS, INSERM and European Community (6° PCRDT: STREP LS HB-CT 2003- 503337). P.M. was supported by grants from the French Ministère de la Recherche et de la Technologie (contract n° ACI JC 5075), Fondation pour la Recherche Médicale (Equipe FRM 2005) and Servier Pharmaceuticals.
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