Epidermal keratinocytes communicate with immune and non-immune cell types through complex signalling networks that are essential for the maintenance of homeostasis and become altered in several highly prevalent skin diseases, such as atopic dermatitis and psoriasis. GRK2 (G protein-coupled Receptor Kinase 2) is a versatile protein that negatively regulates signalling mediated by G Protein-Coupled Receptors (GPCR) superfamily and also modulates multiple non-GPCR cellular partners through phosphorylation and/or interaction. How these canonical and non-canonical GRK2 interaction networks are engaged and can contribute to the physiological and pathological roles of this kinase is of particular interest. In addition, the host laboratory has described a relevant role for GRK2 in the safeguard of the epithelial phenotype in stratified epithelia. Furthermore, we have recently generated a mouse model of keratinocyte-specific GRK2 deletion (GRK2 eKO) that exhibits a proinflammatory phenotype, suggesting that this kinase plays an essential role in maintaining epidermal homeostasis and in the communication between keratinocytes and immune cells. Therefore, we will first delve into the molecular mechanisms underlying the inflammation-prone phenotype of GRK2 eKO mice, focusing both on MALT1-dependent inflammatory pathways and on kallikreins, proteases with a relevant function in epidermal homeostasis. Moreover, we will explore if GRK2 silencing could potentially enhance susceptibility to inflammatory insults associated with certain cutaneous diseases. We will also analyze which pathological stimuli lead to a lower expression of this kinase in vivo in keratinocytes. In this sense, different experimental approaches will be proposed for the molecular characterization of the phenotype observed in our experimental mouse model and for the study and identification of new GRK2 interactomes. In conclusion, the relevance of this project lies in its contribution to enhance our understanding of the maladaptive rewiring of such regulatory networks under pathological conditions of highly prevalent diseases and with a high social impact.