The complex intercommunication among cell types in their specific tissue environment or via organ crosstalk is essential for homeostasis, while alterations in such interplays lead to pathological situations. The aim of our group is to better understand the role of key signaling nodes in the maladaptive rewiring of cellular communication pathways in disease, with emphasis on G protein-coupled receptor kinase 2 (GRK2) hub. GRK2 levels are altered in humans in prevalent cardiovascular and metabolic pathologies and in certain tumors. Therefore, understanding the molecular basis of such changes in GRK2 expression and its functional impact on cellular processes is critical to assess the feasibility of GRK2 as a useful diagnostic biomarker and/or of new therapeutic strategies based on the modulation of the activity, levels or specific interactions of this protein. In addition to its canonical role as GPCR regulator, GRK2 can directly interact with and/or phosphorylate non-GPCR components of transduction cascades. Our laboratory has pioneered the research on the characterization of different GRK2 interactomes, unveiled new mechanisms of regulation of GRK2 activity, expression and protein stability, uncovered new GRK2 substrates and interacting proteins, and first reported the participation of GRK2 in several relevant cellular processes and patho-physiological situations (angiogenesis, breast cancer, hypertension, cell cycle, cell migration, cardiac and whole-body insulin resistance). By using cellular and mouse models with altered GRK2 dosage (including tamoxifen-induced, tissue-specific deficient and/or mutant knock-in mice), we aim to gain insight on the stimuli and mechanisms triggering changes in GRK2 expression/functionality, on the impact of altering GRK2 in disease initiation and/or progression, and on the phenotypic integration of canonical and non-canonical GRK2 functions, both cell type- and tissue microenvironment-specific, in pathological conditions.