Échafaudages protéiques et signalisation modulaire via les récepteurs à sept domaines transmembranaires : au-delà des protéines G.

Abstract

Jusqu'à récemment, la cascade d'activation des récepteurs couplés aux protéines G (RCPG) semblait être linéaire et n'impliquer que les protéines G hétérotrimériques. De nouveaux partenaires ainsi que de nouvelles voies de signalisation sont aujourd'hui identifiés. Ainsi, les kinases spécifiques aux RCPG et les arrestines, impliquées dans leur découplage des protéines G, semblent aussi activer d'autres voies de signalisations en servant de protéines adaptatrices ou effectrices. L'interaction directe entre les RCPG et des petites protéines G (Rho, ARF), des canaux ioniques, ou encore des protéines d'échafaudages via des motifs spécifiques (SH2, SH3), suggère aussi l'existence de voies de signalisation alternatives. Enfin, ces récepteurs peuvent exister sous forme homo- ou hétérodimérique et des protéines chaperons peuvent moduler l'expression et la spécificité de certains de leurs ligands.

G protein coupled receptors (GPCR) represent one of the largest families of proteins encoded by the human genome. They mediate cellular communications important in many fundamental processes. Until recently, GPCR function was thought to be mediated almost exclusively via the obligatory activation of hetero-trimeric G proteins. The development of molecular biological approaches and methods to assess protein-protein interactions have now markedly broadened this view. It is now apparent that proteins such as receptor kinases and arrestins, which quench the signaling function of GPCR, are themselves capable of functioning either as effecters or adaptors that initiate and regulate non-conventional signaling pathways or cell biological processes involved in receptor function. Similarly, the direct interaction of GPCR either through specific sequence motifs, or conformations with small molecular weight G proteins, enzymes, ion channels or scaffolding proteins indicates a larger than expected diversity in the physiological processes affected this receptor family. Finally, realization that homo- and hetero-dimerization of GPCR as well as interactions with escort proteins can influence their processing, trafficking, ligand binding and signaling specificity points to levels of complexity and diversity that were unsuspected. Unraveling the molecular principles of these interactions and their physiological relevance provides new challenges that will undoubtedly reveal novel targets for the development of therapeutic interventions. [References: 45]