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. 2016 May 16:14:28-37.
eCollection 2016 May.

Dual role of GRK5 in cancer development and progression

J Gambardella  1 , A Franco  2 , C Del Giudice  2 , A Fiordelisi  2 , E Cipolletta  1 , M Ciccarelli  1 , B Trimarco  2 , G Iaccarino  1 , D Sorriento  3
Affiliations

Dual role of GRK5 in cancer development and progression

J Gambardella et al. Transl Med UniSa. .

Abstract

GRK5 is a multifunctional protein that is able to move within the cell in response to various stimuli to regulate key intracellular signaling from receptor activation, on plasmamembrane, to gene transcription, in the nucleus. Thus, GRK5 is involved in the development and progression of several pathological conditions including cancer. Several reports underline the involvement of GRK5 in the regulation of tumor growth even if they appear controversial. Indeed, depending on its subcellular localization and on the type of cancer, GRK5 is able to both inhibit cancer progression, through the desensitization of GPCR and non GPCR-receptors (TSH, PGE2R, PDGFR), and induce tumor growth, acting on non-receptor substrates (p53, AUKA and NPM1). All these findings suggest that targeting GRK5 could be an useful anti-cancer strategy, for specific tumor types. In this review, we will discuss the different effects of this kinase in the induction and progression of tumorigenesis, the molecular mechanisms by which GRK5 exerts its effects, and the potential therapeutic strategies to modulate them.

Keywords: GPCR; GRK5; cancer.

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Figures

Figure 1:
Figure 1:
TIG-1 inhibits PGE2-dependent cell proliferation through the induction of GRK5 expression
Figure 2.
Figure 2.
GRK5 inhibits tumor growth through phosphorylation of GPCR A) GPCRs are activated through the interaction with a specific ligand. The activated receptor, through G-protein, stimulates proliferative signaling. B–C) GRK5 interacts (B) and phosphorylates (C) GPCR, promoting un-coupling of G-protein and inhibition of proliferative signaling.
Figure 3.
Figure 3.
GRK5 promotes p53 degradation GRK5 interacts with and phosphorylates p53 leading to an increase of p53-MDM2 interaction, which on turn induces poliubiquitination and degradation of p53.
Figure 4.
Figure 4.
GRK5 promotes cytoskeleton remodeling inducing cancer cell migration and invasion. In the inactive form of ERM-complex, the COOH and NH domains interact, determining a close conformation of the complex. GRK5 phosphorylates an ERM-component (Moesin), interrupting this intra-molecular interaction and activating ERM-complex. In the activated form of the ERM- complex, the COOH domain interacts with cytoskeleton while the NH domain interacts with plasma membrane, inducing cytoskeleton remodeling and, consequently, cell migration and invasion.
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References

    1. Pitcher JA, Freedman NJ, Lefkowitz RJ. “G protein-coupled receptor kinases,”. Annu Rev Biochem. 1998;67:653–92. - PubMed
    1. Reiter E, Lefkowitz RJ. “GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling,”. Trends Endocrinol Metab. 2006 May-Jun;17:159–65. - PubMed
    1. Tiberi M, Nash SR, Bertrand L, Lefkowitz RJ, Caron MG. “Differential regulation of dopamine D1A receptor responsiveness by various G protein-coupled receptor kinases,”. J Biol Chem. 1996 Feb 16;271:3771–8. - PubMed
    1. Gainetdinov RR, Bohn LM, Walker JK, Laporte SA, Macrae AD, Caron MG, Lefkowitz RJ, Premont RT. “Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice,”. Neuron. 1999 Dec;24:1029–36. - PubMed
    1. Aramori I, Ferguson SS, Bieniasz PD, Zhang J, Cullen B, Cullen MG. “Molecular mechanism of desensitization of the chemokine receptor CCR-5: receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor,”. EMBO J. 1997 Aug 1;16:4606–16. - PMC - PubMed

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