Pathophysiological roles of G-protein-coupled receptor kinases

G-protein-coupled receptor kinase 2 (GRK2) is a central regulator of G-protein-coupled receptor signaling. We report that Mdm2, an E3-ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by β2-adrenergic receptor stimulation and β-arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2-deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin-like growth factor-1 alters Mdm2-mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions.

/pdf/mdm2-is-involved-in-the-ubiquitination-and-degradation-of-g-g62qxqsff6.pdf

Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2.

Numerous factors partake in the fine-tuning of arterial blood pressure. The heptahelical G-protein-coupled receptors (GPCRs) represent one of the largest classes of cell-surface receptors. Further, ligands directed at GPCRs account for nearly 30 % of current clinical pharmaceutical agents available. Given the wide variety of GPCRs involved in blood pressure control, it is reasonable to speculate for a potential role of established intermediaries involved in the GPCR desensitization process, like the G-protein-coupled receptor kinases (GRKs), in the regulation of vascular tone. Of the seven mammalian GRKs, GRK2 seems to be the most relevant isoform at the cardiovascular level. This review attempts to assemble the currently available information concerning GRK2 and hypertension, opening new potential fields of translational investigation to treat this vexing disease.

G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms.

https://academiccommons.columbia.edu/doi/10.7916/D81Z4GF4/download

Adrenergic signaling in heart failure and cardiovascular aging.

Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein.

https://molpharm.aspetjournals.org/content/molpharm/91/3/159.full.pdf

Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules.

Granulosa cell tumors are serious ovarian neoplasms that can occur in women of all ages. While there have been numerous attempts to understand the cause of these malignancies, the pathogenesis of granulosa cell tumors (GCTs) still remains largely unknown. G-protein coupled receptor kinases (GRKs) are important regulators of signal transduction through the process of receptor desensitization and internalization. Receptors that are regulated by GRKs are members of the large family of seven-transmembrane receptors and include the follicle stimulating hormone receptor (FSHR). In granulosa cells, the FSH signaling system is responsible for cell proliferation, differentiation, and steroidogenesis. In the studies presented, we examined GRK mRNA and protein expression in nonmalignant human granulosa cells, in KGN cells, a human GCT cell line, and in a panel of human GCT samples. The KGN tumor cells express significantly less GRK4 alpha/beta protein and higher levels of GRK2 and GRK4 gamma/delta protein as compared to nonmalignant human granulosa cells. In human GCT samples, GRK4 alpha/beta protein was detected in 3 of the 13 tumor samples, whereas gamma/delta proteins expression was detected in all samples. These findings suggest that GRK protein expression is altered in GCTs and may be involved in the pathogenesis of these tumors.

Differential expression of GRK isoforms in nonmalignant and malignant human granulosa cells

Posttranslational processing of the pro-growth hormone-releasing hormone (proGHRH) peptide can result in the formation of at least two peptide products: GHRH and the C-terminal peptide, GHRH-related peptide (GHRH-Rp). While cyclic adenosine monophosphate transduces many of the actions of GHRH, other pathways also have been implicated in its actions. The aims of this study were to examine and characterize the activation of mitogen-activated protein kinase (MAPK) pathways by GHRH, and GHRH-RP in pituitary-derived GH3 cells, as well as the activation of the transcription factors that serve as substrates for these kinases. GHRH rapidly increased p44/p42 MAPK activity in GH3 cells in a protein kinase A-dependent and a protein kinase C-independent manner and stimulated the activation of the transcription factor Elk-1. By contrast, GHRH-RP, and p75-92NH2 had no effect on p44/p42 MAPK phosphorylation in these cells. Additionally, we determined that all three peptides, GHRH, GHRH-RP, and p75-92NH2, rapidly and specifically increase phosphorylation of p38 MAPK and stimulate the activation of the nuclear factor CHOP. These are the first studies to demonstrate the activation of Elk-1 by GHRH and the activation of p38 MAPK and CHOP by GHRH, GHRH-RP, and p75-92NH2. We conclude, that members of the GHRH family of peptides differentially activate multiple intracellular signaling pathways and suggest that the biologic actions of GHRH may be far more diverse than previously thought.

Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells.

The GH-releasing hormone (GHRH) precursor molecule contains a 30-amino acid C-terminal region that has been designated GHRH-related peptide (GHRH-RP). To begin to understand the physiological role of GHRH-RP, transgenic (Tg) mice that constituitively express this peptide were developed. To generate these mice, a transgene (SS-RP) was constructed by overlap primer extension PCR. This transgene, under the control of the mouse phosphoglycerate kinase gene, selectively expresses GHRH-RP, but not GHRH. Western blot analysis confirmed that the transgene produces GHRH-RP. Animals were evaluated for the effect of excess GHRH-RP on growth, fertility, behavior, stem cell factor (SCF) expression, and hematopoiesis. Northern blot and RT-PCR were used to demonstrate ubiquitous expression of the transgene in tissues from GHRH-RP Tg animals. These tissues also had marked overexpression of SCF messenger RNA compared with controls. Tg animals had significantly increased cell cycling for granulocyte-macrophage, erythroid, ...

/pdf/development-of-a-transgenic-mouse-that-overexpresses-a-novel-2cjj0coz8f.pdf

Development of a transgenic mouse that overexpresses a novel product of the growth hormone-releasing hormone gene.

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Differential expression of GRK isoforms in nonmalignant and malignant human granulosa cells

Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells.

Development of a transgenic mouse that overexpresses a novel product of the growth hormone-releasing hormone gene.