G Protein-coupled Receptor Kinase 5 Is Localized to Centrosomes and Regulates Cell Cycle Progression

Michal, Allison M.; So, Christopher H.; Beeharry, Neil; Shankar, Haripriya; Mashayekhi, Rouzbeh; Yen, Tim J.; Benovic, Jeffrey L.

doi:10.1074/jbc.m111.298034

Cited by 36 publications

(39 citation statements)

References 47 publications

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“…Screening with shRNA library identified GRK5 as a potential regulator of cell-cycle progression (13), and GRK5 expression levels correlate with prostate cell proliferation in vitro and tumor growth in animals (14). Biochemically, depletion of GRK5 expression resulted in G 2 -M arrest in prostate (14) and breast (15) cancer cells, reinforcing the idea that GRK5 regulates the cell-cycle progression.…”

Section: Introductionmentioning

confidence: 70%

G Protein–Coupled Receptor Kinase GRK5 Phosphorylates Moesin and Regulates Metastasis in Prostate Cancer

et al. 2014

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G protein-coupled receptor kinases (GRK) regulate diverse cellular functions ranging from metabolism to growth and locomotion. Here, we report an important contributory role for GRK5 in human prostate cancer. Inhibition of GRK5 kinase activity attenuated the migration and invasion of prostate cancer cells and, concordantly, increased cell attachment and focal adhesion formation. Mass spectrometric analysis of the phosphoproteome revealed the cytoskeletal-membrane attachment protein moesin as a putative GRK5 substrate. GRK5 regulated the subcellular distribution of moesin and colocalized with moesin at the cell periphery. We identified amino acid T66 of moesin as a principal GRK5 phosphorylation site and showed that enforcing the expression of a T66-mutated moesin reduced cell spreading. In a xenograft model of human prostate cancer, GRK5 silencing reduced tumor growth, invasion, and metastasis. Taken together, our results established GRK5 as a key contributor to the growth and metastasis of prostate cancer. Cancer Res; 74(13); 3489-500. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 70%

G Protein–Coupled Receptor Kinase GRK5 Phosphorylates Moesin and Regulates Metastasis in Prostate Cancer

et al. 2014

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“…Phosphorylation at Thr-199 by cyclin-dependent kinase 1 is involved in regulating the centrosome (33), whereas the phosphorylation of both Ser-4 and Thr-199 controls centrosome duplication (33,46). Interestingly, GRK5 is also localized in the centrosome, although it does not appear to regulate centrosomal duplication (16). Nevertheless, knockdown of GRK5 leads to increased apoptosis associated with PLK1 inhibition, suggesting interplay between GRK5 and PLK1 in regulating the phosphorylation of NPM1 and controlling normal cell function.…”

Section: Discussionmentioning

confidence: 95%

“…Cells were then selected in 2 g/ml puromycin (Sigma) to obtain a stably expressing population as previously described (16). HeLa cells with stable GRK5 knockdown were grown in DMEM supplemented with 10 mM HEPES, 10% FBS, and 2 g/ml puromycin.…”

Section: Methodsmentioning

confidence: 99%

“…Some examples of non-GPCR substrates include tubulin (4,5), synucleins (6), phosducin (7), DREAM (8), p38 (9), IB␣ (10), NFB1 p105 (11), ezrin (12), HDAC5 (13), ␤-arrestin-1 (14), p53 (15,16), and Hip (17). These additional activities may be important because GRK levels vary in many pathological conditions including cardiovascular disease (18 -21), cancer (22)(23)(24)(25), and various neurological disorders (26 -29).…”

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confidence: 99%

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G Protein-coupled Receptor Kinase 5 Phosphorylates Nucleophosmin and Regulates Cell Sensitivity to Polo-like Kinase 1 Inhibition

Michal

Mashayekhi

et al. 2012

Journal of Biological Chemistry

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Background: G protein-coupled receptor kinases (GRKs) are important regulators of receptor signaling although little is known about their functions beyond their receptor modifying activities. Results: GRK5 binds and phosphorylates nucleophosmin. Conclusion: GRK5 and polo-like kinase 1 coordinately regulate nucleophosmin phosphorylation and cell sensitivity to inhibitor-induced apoptosis. Significance: GRKs play an important role in regulating normal cell functions such as cell cycle regulation and apoptosis.

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“…A number of enzyme inducers that exhibit hepatocarcinogenicity commonly induce hepatocellular proliferation and proliferative lesions, such as hepatocellular-altered foci, adenomas, and carcinomas (Cohen, 2010). Grk5, which was included in 10 probe sets, is a kinase of p53 that negatively regulates p53-mediated signal transduction and inhibits apoptosis and cell cycle progression (Chen et al, 2010;Michal et al, 2012). Probe sets that were regulated at doses greater than TD50 in WY numbered 451 and CFB numbered 152.…”

Section: Selection Of Gene Marker Setsmentioning

confidence: 99%

Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets

Kanki

Fujioka

et al. 2016

J. Toxicol. Sci.

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-Several studies have successfully detected hepatocarcinogenicity in rats based on gene expression data. However, prediction of hepatocarcinogens with certain mechanisms of action (MOAs), such as enzyme inducers and peroxisome proliferator-activated receptor α (PPARα) agonists, can prove difficult using a single model and requires a highly toxic dose. Here, we constructed a model for detecting non-genotoxic (NGTX) hepatocarcinogens and predicted their MOAs in rats. Gene expression data deposited in the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) was used to investigate gene marker sets. Principal component analysis (PCA) was applied to discriminate different MOAs, and a support vector machine algorithm was applied to construct the prediction model. This approach identified 106 probe sets as gene marker sets for PCA and enabled the prediction model to be constructed. In PCA, NGTX hepatocarcinogens were classified as follows based on their MOAs: cytotoxicants, PPARα agonists, or enzyme inducers. The prediction model detected hepatocarcinogenicity with an accuracy of more than 90% in 14-and 28-day repeated-dose studies. In addition, the doses capable of predicting NGTX hepatocarcinogenicity were close to those required in rat carcinogenicity assays. In conclusion, our PCA and prediction model using gene marker sets will help assess the risk of hepatocarcinogenicity in humans based on MOAs and reduce the number of two-year rodent bioassays.

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G Protein-coupled Receptor Kinase 5 Is Localized to Centrosomes and Regulates Cell Cycle Progression

Cited by 36 publications

References 47 publications

G Protein–Coupled Receptor Kinase GRK5 Phosphorylates Moesin and Regulates Metastasis in Prostate Cancer

G Protein–Coupled Receptor Kinase GRK5 Phosphorylates Moesin and Regulates Metastasis in Prostate Cancer

G Protein-coupled Receptor Kinase 5 Phosphorylates Nucleophosmin and Regulates Cell Sensitivity to Polo-like Kinase 1 Inhibition

Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets

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