Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins

Black, Joseph B.; Premont, Richard T.; Daaka, Yehia

doi:10.1016/j.semcdb.2015.12.015

Cited by 46 publications

(42 citation statements)

References 96 publications

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“…Once a ligand binds to a GPCR, GRKs sense the intracellular conformational changes as it separates from coupled G protein subunits. They can then phosphorylate the C-terminus of the target GPCR 42 . Phosphorylation will then induce additional GPCR conformational changes and increase its affinity for arrestins.…”

Section: Role Of Grks In Gpcr Signaling Pathwaymentioning

confidence: 99%

The Role of G Protein-coupled Receptor Kinases in Cancer

Yu¹,

Sun²,

Jiao³

et al. 2018

Int. J. Biol. Sci.

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G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. Emerging evidence demonstrates that signaling through GPCRs affects numerous aspects of cancer biology such as vascular remolding, invasion, and migration. Therefore, development of GPCR-targeted drugs could provide a new therapeutic strategy to treating a variety of cancers. G protein-coupled receptor kinases (GRKs) modulate GPCR signaling by interacting with the ligand-activated GPCR and phosphorylating its intracellular domain. This phosphorylation initiates receptor desensitization and internalization, which inhibits downstream signaling pathways related to cancer progression. GRKs can also regulate non-GPCR substrates, resulting in the modulation of a different set of pathophysiological pathways. In this review, we will discuss the role of GRKs in modulating cell signaling and cancer progression, as well as the therapeutic potential of targeting GRKs.

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Section: Role Of Grks In Gpcr Signaling Pathwaymentioning

confidence: 99%

The Role of G Protein-coupled Receptor Kinases in Cancer

Yu¹,

Sun²,

Jiao³

et al. 2018

Int. J. Biol. Sci.

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“…Hence, it is reasonable to suggest that UPEC CM contains protease activity able to cleave pro-EGF on the extracellular side of the host BEC plasma membrane, leading to the release of active EGFR ligands. It is equally plausible that UPEC CM contains GPCR ligand agonists (41,42) that promote a GPCR 3 EGFR transactivation signal. Support for the existence of a CM-activatable host cell receptor comes from the kinetics profile for p-Akt; stimulation with CM promoted the time-dependent increase and then decrease to a basal level of p-Akt.…”

Section: Multistep Bacterial Invasionmentioning

confidence: 99%

Uropathogenic Escherichia coli invades bladder epithelial cells by activating kinase networks in host cells

Kim

Shea²,

Kim³

et al. 2018

Journal of Biological Chemistry

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Uropathogenic (UPEC) is the causative bacterium in most urinary tract infections (UTIs). UPEC cells adhere to and invade bladder epithelial cells (BECs) and cause uropathogenicity. Invading UPEC cells may encounter one of several fates, including degradation in the lysosome, expulsion to the extracellular milieu for clearance, or survival as an intracellular bacterial community and quiescent intracellular reservoir that can cause later infections. Here we considered the possibility that UPEC cells secrete factors that activate specific host cell signaling networks to facilitate the UPEC invasion of BECs. Using GFP-based reporters and Western blot analysis, we found that the representative human cystitis isolate UTI89 and its derivative UTI89ΔFimH, which does not bind to BECs, equally activate phosphatidylinositol 4,5-bisphosphate 3-OH kinase (PI3K), Akt kinase, and mTOR complex (mTORC) 1 and 2 in BECs. We also found that conditioned medium taken from UTI89 and UTI89ΔFimH cultures similarly activates epidermal growth factor receptor (EGFR), PI3K, Akt, and mTORC and that inhibition of EGFR and mTORC2, but not mTORC1, abrogates UTI89 invasion and in animal models of UTI. Our results reveal a key molecular mechanism of UPEC invasion and the host cells it targets, insights that may have therapeutic utility for managing the ever-increasing number of persistent and chronic UTIs.

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“…6 and 7) showing increases with age in hepatic protein levels of GRK2/3 and ␤arr2. Rapid signal termination of agonist-activated GPCRs occurs via GRK-and ␤arr-mediated receptor desensitization and sequestration/internalization, whereas in response to prolonged agonist exposure receptors undergo downregulation by complex processes involving proteolytic degradation within lysosomes (4,53). In the case of ␤ 2 -ARs, downregulation appears to be initiated by typical GRK-mediated receptor phosphorylation and binding of the phosphorylated receptor to the ␤arr2 adaptor protein, followed by ␤ 2 -AR internalization and degradation requiring ubiquitination of ␤arr2 and ␤ 2 -AR, respectively; it should be noted that ubiquitin-dependent lysosomal degradation of ␤ 2 -ARs is of no clear relationship to the oxygen-dependent process of proteasomal degradation described above (48,56).…”

Section: R579mentioning

confidence: 99%

Altered expression of hepatic β-adrenergic receptors in aging rats: implications for age-related metabolic dysfunction in liver

Shi

Shu

Wang

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study, we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand-binding studies demonstrated that β-AR density increased by greater than threefold in hepatocyte membranes from senescent (24-mo-old) compared with young adult (7-mo-old) rats and that this phenomenon was blocked by food restriction, which is known to retard aging processes in rodents. Competition-binding studies revealed a mixed population of β- and β-AR subtypes in liver membranes over the adult life span, with a trend for greater β-AR density with age. Expression of both β-AR subtype mRNAs in rat liver increased with age, whereas β- but not β-AR protein levels declined in livers of old animals. Immunoreactive β- but not β-ARs were preferentially distributed in pericentral hepatic regions. Levels of GRK2/3 and β-arrestin 2 proteins, which are involved in downregulation of agonist-activated GPCRs, including β-ARs, increased during aging. Insofar as sympathetic tone increases with age, our findings suggest that, despite enhanced agonist-mediated downregulation of hepatic β-ARs preferentially affecting the β-AR subtype, increased generation of both receptor subtypes during aging augments the pool of plasma membrane-bound β-ARs coupled to AC in hepatocytes. This study thus identifies one or both β-AR subtypes as possible therapeutic targets involved in aberrant hepatic processes of glucose and lipid metabolism during aging.

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Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins

Cited by 46 publications

References 96 publications

The Role of G Protein-coupled Receptor Kinases in Cancer

The Role of G Protein-coupled Receptor Kinases in Cancer

Uropathogenic Escherichia coli invades bladder epithelial cells by activating kinase networks in host cells

Altered expression of hepatic β-adrenergic receptors in aging rats: implications for age-related metabolic dysfunction in liver

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