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Review
. 2010 Jun;160(4):821-32.
doi: 10.1111/j.1476-5381.2010.00727.x.

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

Petronila Penela  1 , Cristina Murga, Catalina Ribas, Vanesa Lafarga, Federico Mayor Jr
Affiliations
Review

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

Petronila Penela et al. Br J Pharmacol. 2010 Jun.

Abstract

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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Figures

Figure 1
Figure 1
The complex GRK2 interactome. In addition to its ‘classical’ role triggering GPCR phosphorylation and β-arrestin binding, GRK2 can modulate cell signalling by interacting with Gαq and Gβγ subunits. Furthermore, emerging evidence indicate that GRK2 phosphoryates diverse non-GPCR substrates and displays a complex network of functional interactions with proteins involved in signal transduction. The P symbol denotes that GRK2 has been shown to phosphorylate the indicated proteins. The molecular target nomenclature in text and figure legends conforms to the British Journal of Pharmacology Guide to Receptors and Channels (Alexander et al., 2008). See text for details. GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase.
Figure 2
Figure 2
GRK2 interactome involved in cell migration. Schematic representation of signalling molecules/pathways relevant for migration that have been shown to functionally interact with GRK2 (Pathway Studio 6.0, ResNet MedScan Database, Ariadne Genomics). GRK2 interacts with diverse receptors, molecular switches, structural proteins, scaffolding molecules and kinases related to cell motility and chemotaxis. The overall effect on cell migration of the different interactions of GRK2 with its partners will be dependent on the cell type and the signalling context. See text for details. GRK, G protein-coupled receptor kinase.
Figure 3
Figure 3
GRK2 interactome involved in the modulation of cell cycle progression. GRK2 is linked to diverse regulatory networks acting at specific stages of the cell cycle. In response to both extrinsic and intrinsic cues, GRK2 protein plays a critical role in driving cell progression through G1/S and G2/M transitions in a kinase-dependent and independent manner. GRK2 is part of an intrinsic pathway that ensures timely progression of cell cycle at G2/M by means of its functional interaction with CDK2/cyclinA and Pin1 (Penela et al., 2010). Such pathway is disrupted upon DNA damage, when GRK2 appears to turn into a pro-arresting factor that promotes increased cell survival and to dampen p53-dependent responses by mechanisms that remain to be established (dotted lines/question mark). On the other hand, GRK2 contributes to the Hedgehog/Smoothened-triggered control of cell proliferation by promoting Smo activity and relieving the Patched-dependent inhibition of cyclin B (Jiang et al., 2009). CDK, cyclin-dependent kinase; GRK, G protein-coupled receptor kinase.
Figure 4
Figure 4
Targeting the GRK2 interactome. A better knowledge of the determinants of the functional interactions of GRK2 with different signalling proteins may help to design novel strategies in order to specifically target GRK2 interfaces with selective partners (receptors, G protein subunits or other components of the GRK2 interactome) relevant for particular cellular functions. The structure of GRK2 in complex with Gβγ and Gαq (Tesmer et al., 2005) is shown. See text for details. GRK, G protein-coupled receptor kinase.
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