Abstract
Although G protein-coupled receptor kinases (GRKs) have long been known to regulate G protein-coupled receptor (GPCR) desensitization, their more recently characterized functions as scaffolds and signalling adapters underscore that this small family of proteins governs a larger array of physiological functions than originally suspected. This review explores how GRKs contribute to the complex signalling networks involved in the migration of immune cells along chemokine gradients sensed by cell surface GPCRs. We outline emerging evidence indicating that the coordinated docking of several GRKs on an active chemokine receptor determines a specific receptor phosphorylation barcode that will translate into distinct signalling and migration outcomes. The guidance cues for neutrophil migration are emphasized based on several alterations affecting GRKs or GPCRs reported to be involved in pathological conditions.
Highlights
Molecular Cues to Physiopathology.G protein-coupled receptor kinases (GRKs) encompass seven protein isoforms that belong to three different subfamilies: the visual subfamily including GRK1 and GRK7, the GRK2 family including GRK2-3 and the GRK4 family composed of the GRK4, -5 and -6 isoforms
GRK2-3 and GRK5-6 proteins are ubiquitously expressed in cells and tissues, while GRK1 and GRK7 are localized in the retina, and GRK4 is mainly localized in the testis [1]
The molecular mechanisms underlying the contribution of GRK expression to immune homeostasis and responses are not completely understood, a large body of evidence reveals a link between these GRK2-3 and GRK5-6 isoforms and the chemokine receptor subfamily of G protein-coupled receptor (GPCR) (Table 1)
Summary
GRK2-3 and GRK5-6 proteins are ubiquitously expressed in cells and tissues, while GRK1 and GRK7 are localized in the retina, and GRK4 is mainly localized in the testis [1] These proteins were initially characterized by their essential and specialized role in the phosphorylation and desensitization of seven transmembrane domain (7TM) receptors coupled to G proteins (GPCRs), the largest family of receptors with many implications in human health and disease. Numerous studies have since established that GRKs engage noncanonical functional and scaffolding interactions with cellular partners and may even act via kinase-independent mechanisms. The mechanisms connecting these dual functions of GRK to control the biological functions of GPCRs are excessively complex and not completely elucidated. We will conclude by discussing the current knowledge of how these molecular cues and the regulation of GRK expression translate into myeloid immune cell trafficking in physiological and pathological contexts
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