G Protein-coupled Receptor Kinase 2 (GRK2) Modulation and Cell Cycle Progression

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jan 19

PMID 20080565

Citations 43

Authors

Petronila Penela

Veronica Rivas

Alicia Salcedo

Federico Mayor Jr

Affiliations

Soon will be listed here.

Abstract

Cell cycle progression requires changes in the activity or levels of a variety of key signaling proteins. G protein-coupled receptor kinase 2 (GRK2) plays a central role in G protein-coupled receptor regulation. Recent research is uncovering its involvement in additional cellular functions, but the potential role of GRK2 in the cell cycle has not been addressed. We report that GRK2 protein levels are transiently down-regulated during the G2/M transition by a mechanism involving CDK2-mediated phosphorylation of GRK2 at Serine670, which triggers binding to the prolyl-isomerase Pin1 and subsequent degradation. Prevention of GRK2 phosphorylation at S670 impedes normal GRK2 down-regulation and markedly delays cell cycle progression. Interestingly, we find that endogenous GRK2 down-regulation is prevented on activation of the G2/M checkpoint by doxorubicin and that stabilized GRK2 levels in such conditions inversely correlate with the p53 response and the induction of apoptosis, suggesting that GRK2 participates in the regulatory network controlling cell cycle arrest and survival in such conditions.

Citing Articles

GRK2-mediated AKT activation controls cell cycle progression and G2 checkpoint in a p53-dependent manner.

Rivas V, Gonzalez-Munoz T, Albitre A, Lafarga V, Delgado-Arevalo C, Mayor Jr F Cell Death Discov. 2024; 10(1):385.

PMID: 39198399 PMC: 11358448. DOI: 10.1038/s41420-024-02143-8.

Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery.

Lu K, Zhou X Sci Signal. 2024; 17(841):eadi8743.

PMID: 38889227 PMC: 11409840. DOI: 10.1126/scisignal.adi8743.

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation.

Jeong J, Usman M, Li Y, Zhou X, Lu K Cells. 2024; 13(9.

PMID: 38727267 PMC: 11083468. DOI: 10.3390/cells13090731.

Exploring the potential biological function of GRK2 in colorectal cancer.

Gao M, Liang X, Fan M, Wu Y, Dong M, Du R Funct Integr Genomics. 2024; 24(2):51.

PMID: 38446273 DOI: 10.1007/s10142-024-01322-1.

Ubiquitination of GRK2 Is Required for the β-Arrestin-Biased Signaling Pathway of Dopamine D2 Receptors to Activate ERK Kinases.

Liu H, Ma H, Zeng X, Wu C, Acharya S, Sudan S Int J Mol Sci. 2023; 24(12).

PMID: 37373182 PMC: 10298151. DOI: 10.3390/ijms241210031.

References

Bliziotes M, GUNNESS M, Zhang X, Nissenson R, Wiren K . Reduced G-protein-coupled-receptor kinase 2 activity results in impairment of osteoblast function. Bone. 2000; 27(3):367-73. DOI: 10.1016/s8756-3282(00)00338-0. View

Metaye T, Gibelin H, Perdrisot R, Kraimps J . Pathophysiological roles of G-protein-coupled receptor kinases. Cell Signal. 2005; 17(8):917-28. DOI: 10.1016/j.cellsig.2005.01.002. View

Bernis C, Vigneron S, Burgess A, Labbe J, Fesquet D, Castro A . Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCF(betatrcp). EMBO Rep. 2006; 8(1):91-8. PMC: 1796751. DOI: 10.1038/sj.embor.7400853. View

Lu K, Zhou X . The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol. 2007; 8(11):904-16. DOI: 10.1038/nrm2261. View

Ho J, Cocolakis E, Dumas V, Posner B, Laporte S, Lebrun J . The G protein-coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction. EMBO J. 2005; 24(18):3247-58. PMC: 1224684. DOI: 10.1038/sj.emboj.7600794. View

Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G . A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol. 2004; 6(4):308-18. DOI: 10.1038/ncb1110. View

Salcedo A, Mayor Jr F, Penela P . Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2. EMBO J. 2006; 25(20):4752-62. PMC: 1618114. DOI: 10.1038/sj.emboj.7601351. View

Wulf G, Liou Y, Ryo A, Lee S, Lu K . Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. J Biol Chem. 2002; 277(50):47976-9. DOI: 10.1074/jbc.C200538200. View

Luttrell L . Composition and function of g protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity. J Mol Neurosci. 2005; 26(2-3):253-64. DOI: 10.1385/JMN:26:2-3:253. View

10.

Peppel K, Jacobson A, Huang X, MURRAY J, Oppermann M, Freedman N . Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells attenuates mitogenic signaling via G protein-coupled and platelet-derived growth factor receptors. Circulation. 2000; 102(7):793-9. DOI: 10.1161/01.cir.102.7.793. View

11.

DeWire S, Ahn S, Lefkowitz R, Shenoy S . Beta-arrestins and cell signaling. Annu Rev Physiol. 2007; 69:483-510. DOI: 10.1146/annurev.physiol.69.022405.154749. View

12.

Penela P, Ribas C, Aymerich I, Eijkelkamp N, Barreiro O, Heijnen C . G protein-coupled receptor kinase 2 positively regulates epithelial cell migration. EMBO J. 2008; 27(8):1206-18. PMC: 2367399. DOI: 10.1038/emboj.2008.55. View

13.

Elorza A, Penela P, Sarnago S, Mayor Jr F . MAPK-dependent degradation of G protein-coupled receptor kinase 2. J Biol Chem. 2003; 278(31):29164-73. DOI: 10.1074/jbc.M304314200. View

14.

Meloni A, Fralish G, Kelly P, Salahpour A, Chen J, Wechsler-Reya R . Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol. 2006; 26(20):7550-60. PMC: 1636865. DOI: 10.1128/MCB.00546-06. View

15.

Goldstone S, Pavey S, Forrest A, Sinnamon J, Gabrielli B . Cdc25-dependent activation of cyclin A/cdk2 is blocked in G2 phase arrested cells independently of ATM/ATR. Oncogene. 2001; 20(8):921-32. DOI: 10.1038/sj.onc.1204177. View

16.

Wulf G, Ryo A, Liou Y, Lu K . The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Res. 2003; 5(2):76-82. PMC: 154150. DOI: 10.1186/bcr572. View

17.

Penela P, Murga C, Ribas C, Salcedo A, Jurado-Pueyo M, Rivas V . G protein-coupled receptor kinase 2 (GRK2) in migration and inflammation. Arch Physiol Biochem. 2008; 114(3):195-200. DOI: 10.1080/13813450802181039. View

18.

Ribas C, Penela P, Murga C, Salcedo A, Garcia-Hoz C, Jurado-Pueyo M . The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochim Biophys Acta. 2006; 1768(4):913-22. DOI: 10.1016/j.bbamem.2006.09.019. View

19.

Penela P, Ribas C, Mayor Jr F . Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal. 2003; 15(11):973-81. DOI: 10.1016/s0898-6568(03)00099-8. View

20.

Lippens G, Landrieu I, Smet C . Molecular mechanisms of the phospho-dependent prolyl cis/trans isomerase Pin1. FEBS J. 2007; 274(20):5211-22. DOI: 10.1111/j.1742-4658.2007.06057.x. View