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The Role of GRK5 in Cancer Development and Progression

GRKs and GRK5

GRKs (G-protein-coupled- receptor kinases) are a family of serine/threonine kinases traditionally known for their ability to recognize and phosphorylate agonist-activated G-protein-coupled receptors (GPCRs), leading to their desensitization. In particular, the agonist-dependent conformational can change of the receptor renders the latter available for GRK-mediated-phosphorylation, lead to G-protein-uncoupling and the increase of GPCR affinity for arrestins and clathrin-dependent receptor internalization. In this way, GRKs act as crucial negative regulators of various GPCRs, including adrenergic receptors, opioid, dopamine, muscarinic receptors and chemokine receptors.

Figure 1. Binding partners with GRKs. GRKs regulate diverse signaling pathways by the interaction with intracellular proteins, resulting in various physiological responses.

Among GRKs, GRK5 is one of the most studied since it is involved in several pathologic conditions. Indeed, GRK5 is up-regulated in failing human myocardium, and its over-expression in the heart reduced cardiac β-AR responsiveness. Several studies underline the involvement of GRK5 in the regulation of glucose metabolism. Indeed, research suggests that the overexpression of GRK5 enhances the internalization of Glucagon Receptor, a GPCR that mediates hyperglycaemic effects of glucagon in Diabetes.

Role of GRK5 in Cancer

Oncogenic phenotype derives from diverse genetic alterations that cause constitutive activation or a loss of function of proteins, such as the loss of allelic heterozygosity. Importantly, chromosome translocation of the 10q24 region has been specifically observed in several tumors, such as thyroid adenoma and glioma, suggesting that alteration of some genes in this region could affect the development of tumors. Since GRK5 maps on chromosome 10, at the q24 region, it is likely that alteration of GRK5 gene, could be involved in certain thyroid or glia tumors. Several reports underline the involvement of GRK5 in the regulation of tumor growth. Moreover, GRK5 can be a potential target for the therapeutic strategies in cancer.

● GRK5 inhibits tumor growth

Several studies show that GRK5 may be a negative regulator of cancer cell proliferation, mainly through its ability to desensitize GPCR on plasma membrane. And researchers have proved that in colon cancer cells HCT116, the expression of Tazarotene-induced gene 1 (TIG-1), a putative tumor suppressor, inhibits cell proliferation by inducing GRK5 expression in response to PGE2. TIG1 can suppress PGE2-stimulated cell proliferation through inhibition of β-catenin pathway, and the effect is mediated by GRK5, since it is ameliorated by GRK5 siRNA. Moreover, the overexpression of GRK5 suppresses PGE2-stimulated β-catenin activation in a dose dependent manner in HCT116 and DLD-1 cells. And in thyroid cancer cells, GRK5 has negative effects on tumor growth, due to its ability to downregulate GPCRs activity, in particular TSH-receptor activity.

● GRK5 regulates p53

An evidence that suggests the ability of GRK5 to promote tumorigenesis, is its ability to inhibits p53, participating to the regulation of genome integrity. p53 is a crucial tumor suppressor that induces cell cycle arrest or apoptosis in response to diverse stresses, and its function is regulated primarily at the level of protein stability through post-translational modifications such as phosphorylation and acetylation. Studies have shown that GRK5 phosphorylates p53 at Thr-55 and promotes its degradation, thus inhibiting p53-mediated apoptosis both in vitro, in cultured human osteosarcoma cells, and in vivo. In particular, GRK5 knockout mice show abnormal p53 levels and enhanced susceptibility in response to irradiation. It is clear that GRK5 also acts as stimulator of pro-tumoral effect in the cell, representing a potential target to attenuate resistance to radiation that characterizes some types of cancer.

Figure 2. A model for the regulation of p53 by GRK5.

● GRK5 phosphorylates moesin

Cancer metastasis involves the cell local invasion and migration so that detached cells from the primary tumor mass can colonize distant organs. Among the molecular mediators of cancer cell migration and invasion, moesin is part of ERM complex (Ezrin-Radixin-Moesin) that links membrane components to actin cytoskeleton, regulating cytoskeleton remodeling and cell adhesions. Studies have demonstrated that GRK5 colocalizes with moesin on the plasma membrane, catalyzes its phosphorylation at T66 residue, and regulates cellular distribution of moesin promoting actin remodeling and, then, invasion and metastasis of PC3 cells. Moreover, in a xenograft model of human prostate cancer, GRK5 silencing reduced tumor growth, invasion and metastasis. Taken together, these results propose GRK5 as a key contributor to the growth and metastasis of prostate cancer.

Targeting GRK5 as potential therapeutic strategy for cancer

The regulation of the expression and activity of GRKs has yielded promising results in the treatment of multiple diseases, from heart failure and diabetes to cancer and inflammatory diseases, in several animal models and cell culture systems. Given the anti-tumoral effect of GRK5 acting on GPCRs, the induction of GRK5 levels could be the effective strategy for the treatment of GPCR-dependent tumors. Several compounds are available that induce CREB activity, a transcription factor that regulates the expression of several genes, including GRK5 gene. Thus the use of these compounds could be effective to induce GRK5 expression in cancer. Studies have been shown that GRK5 inhibits HDAC5 in the nucleus, promoting MEF2 expression in cardiac myocytes. Given the main role of this enzymes in cancer progression and the use of HDAC inhibitors as anticancer drugs, it could be interesting to evaluate such phenomenon also in tumor cells. And an innovative strategy has been proposed that is specific for cancer and is based on a competitive interaction with GRK5 cytosolic substrates rather than inhibition of its activity, the TAT-RH peptide.

Future prospective

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 plasma membrane, to gene transcription, in the nucleus. Therefore, GRK5 is involved in the development and progression of several pathological conditions such as cardiac hypertrophy and failure, diabetes and cancer. The proof of concept that GRK5 is involved in the regulation of cancer progression derives from the discovery that GRK5 is part of a subset of gene targets required for mitotic progression in human cancer cells. However, its role in tumor growth is still ambiguous and complex, since GRK5 exerts opposite effects, depending on tumor cell type and kinase localization within the cell. Therefore, further researches will be needed to better define the nuclear effects of GRK5 and the possibility to regulate its subcellular localization in order to regulate its functions within the tumor cell as necessary.


  1. Gambardella J, et al. Dual role of GRK5 in cancer development and progression. Translational Medicine, 2016, 14:28-37.
  2. Kim J I, et al. G-protein coupled receptor kinase 5 regulates prostate tumor growth. Journal of Urology, 2012, 187(1):322-329.
  3. Chen X, et al. G-protein-coupled Receptor Kinase 5 Phosphorylates p53 and Inhibits DNA Damage-induced Apoptosis. Journal of Biological Chemistry, 2010, 285(17):12823-30.
  4. Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nature Reviews Drug Discovery, 2011, 10(1):47.
For research use only. Not intended for any clinical use.

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