The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets

Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma, Madrid, Spain.
British Journal of Pharmacology (Impact Factor: 4.84). 06/2010; 160(4):821-32. DOI: 10.1111/j.1476-5381.2010.00727.x
Source: PubMed


GRK2 is a ubiquitous member of the G protein-coupled receptor kinase (GRK) family that appears to play a central, integrative role in signal transduction cascades. GRKs participate together with arrestins in the regulation of G protein-coupled receptors (GPCR), a family of hundreds of membrane proteins of key physiological and pharmacological importance, by triggering receptor desensitization from G proteins and GPCR internalization, and also by helping assemble macromolecular signalosomes in the receptor environment acting as agonist-regulated adaptor scaffolds, thus contributing to signal propagation. In addition, emerging evidence indicates that GRK2 can phosphorylate a growing number of non-GPCR substrates and associate with a variety of proteins related to signal transduction, thus suggesting that this kinase could also have diverse 'effector' functions. We discuss herein the increasing complexity of such GRK2 'interactome', with emphasis on the recently reported roles of this kinase in cell migration and cell cycle progression and on the functional impact of the altered GRK2 levels observed in several relevant cardiovascular, inflammatory or tumour pathologies. Deciphering how the different networks of potential GRK2 functional interactions are orchestrated in a stimulus, cell type or context-specific way is critical to unveil the contribution of GRK2 to basic cellular processes, to understand how alterations in GRK2 levels or functionality may participate in the onset or development of several cardiovascular, tumour or inflammatory diseases, and to assess the feasibility of new therapeutic strategies based on the modulation of the activity, levels or specific interactions of GRK2.

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    • "GRK2 is a Ser/Thr kinase that has been classically named and widely studied for its role in the regulation and desensitization of G protein-coupled receptors (GPCRs). Besides such a canonical role, recent data indicate that GRK2 is also able to phosphorylate a variety of non-GPCR substrates (Penela et al., 2010; Ribas et al., 2007). In addition, changes in GRK2 expression and activity have been identified in several relevant inflammatory, metabolic, cardiovascular or cancer diseases, suggesting that those alterations may contribute to the onset or development of these pathologies (Gurevich et al., 2012). "
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    • "While probably the mH 1 R-dependent activation of p38 MAPK still relies on the elevated[Ca 2+ ]i , a mH 4 R-emerging alternate pathway is enhancing p38 MAPK activity. Thus, the interaction of mH 1 R and mH 4 R in terms of induction of p38 MAPK activation remains to be elucidated, the G-protein coupled receptor kinases 2 being a potential target[52]. The transcription factor CREB (cAMP responsive element binding protein) is also activated by means of mH 1 R and mH 4 R. "
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    • "In addition to its classical function as a GPCR kinase, GRK2 can phosphorylate non-GPCR substrates including various receptor tyrosine kinases, structural proteins (e.g., tubulin), and intracellular signaling proteins (Penela et al., 2010). GRK2 can also regulate the function of receptors and other proteins in a kinase-independent manner through direct physical association (Penela et al., 2010). The combination of its classical and "
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