The process by which G protein-coupled receptors (GPCRs) are internalized through the clathrin-coated vesicles involves interactions of multifunctional adaptor proteins. These interactions are tightly controlled by phosphorylation and dephosphorylation mechanisms resulting in the regulation of receptor endocytosis. However, the identities of the kinases involved in this process remained largely unknown until recently. This paper discusses advances in our knowledge of the important role played by protein phosphorylation in the regulation of the endocytic machinery and how phosphorylation controls the coated vesicle cycle. 1. An Overview on G Protein-Coupled Receptors (GPCRs) Internalization Reversible protein phosphorylation by the interplay between kinases and phosphatases is a major regulatory mechanism for G protein-coupled receptors (GPCRs) internalization [1–3]. Therefore, the aim of this paper is to synthesise our understanding of the phosphorylation mechanisms regulating GPCRs internalization. Growing interest in this field is due to the involvement of GPCRs in the regulation of a number of functions. Following their activation, these receptors enter inside the cells, a process named receptor internalization. This process requires receptor desensitization which is achieved by receptor phosphorylation, sequestration and internalization. In this manner, receptors are removed from the surface and transferred into cells. Inside the cells, receptors are embedded into small membrane vesicles (endosomes) which may be recycled back to the plasma membrane in order to renew their fully functional coupling with proteins and effectors (i.e., resensitization). GPCRs expression can also be regulated by a process of downregulation which is a terminal stage of receptor life where receptors are degraded in lysosomes. However, it is now becoming apparent that GPCRs can also be regulated independently of their phosphorylation state (reviewed in [4]). Before starting the role played by phosphorylation during receptor internalization, a brief review of the different steps controlling receptor internalization will be given. 1.1. Steps Conducting to Receptor Internalization The current proposed model for GPCRs internalization is essentially based on β2-adrenergic receptor (β2-AR) studies. Briefly, following agonist stimulation, GPCRs undergo conformational change that allow binding of G proteins, leading to the activation of different effectors and signaling pathways [5]. The desensitization process is then activated (Figure 1). One of the first steps involves the
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