title: G protein-coupled receptor kinase 2 (GRK2) is localized to centrosomes and mediates epidermal growth factor-promoted centrosomal separation.
abstract: G protein-coupled receptor kinases (GRKs) play a central role in regulating receptor signaling, but recent studies suggest a broader role in modulating normal cellular functions. For example, GRK5 has been shown to localize to centrosomes and regulate microtubule nucleation and cell cycle progression. Here we demonstrate that GRK2 is also localized to centrosomes, although it has no role in centrosome duplication or microtubule nucleation. Of interest, knockdown of GRK2 inhibits epidermal growth factor receptor (EGFR)-mediated separation of duplicated centrosomes. This EGFR/GRK2-mediated process depends on the protein kinases mammalian STE20-like kinase 2 (Mst2) and Nek2A but does not involve polo-like kinase 1. In vitro analysis and dominant-negative approaches reveal that GRK2 directly phosphorylates and activates Mst2. Collectively these findings demonstrate that GRK2 is localized to centrosomes and plays a central role in mitogen-promoted centrosome separation most likely via its ability to phosphorylate Mst2.
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: So
authors.forename: Allison
authors.initials: A
authors.lastname: Michal
authors.forename: Konstantin E
authors.initials: KE
authors.lastname: Komolov
authors.forename: Jiansong
authors.initials: J
authors.lastname: Luo
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D018385:Centrosome / Q000187:drug effects* / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008969:Molecular Sequence Data; D000072379:NIMA-Related Kinases; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D000090742:Serine-Threonine Kinase 3; D000099317:Hippo Kinases
chemical_list: D004815:Epidermal Growth Factor; D054769:G-Protein-Coupled Receptor Kinase 2; D000072379:NIMA-Related Kinases; D010748:Phosphopeptides; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C089441:NEK2 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases
references.citation: J Biol Chem. 1999 Aug 20;274(34):24328-34
references.pmid: 10446210
references.citation: J Biol Chem. 2010 Apr 23;285(17):12823-30
references.pmid: 20124405
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12457-62
references.pmid: 18711143
references.citation: J Biol Chem. 1999 Nov 26;274(48):34411-6
references.pmid: 10567420
references.citation: J Biol Chem. 2006 Nov 10;281(45):34159-70
references.pmid: 16980301
references.citation: Curr Biol. 2011 Jul 12;21(13):1145-51
references.pmid: 21723128
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7
references.pmid: 18669648
references.citation: Curr Biol. 2007 Feb 20;17(4):316-22
references.pmid: 17291758
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1118-23
references.pmid: 20080565
references.citation: Nat Cell Biol. 2010 Dec;12(12):1166-76
references.pmid: 21076410
references.citation: J Biol Chem. 2001 Jun 1;276(22):19276-85
references.pmid: 11278283
references.citation: J Proteome Res. 2011 Mar 4;10(3):1126-38
references.pmid: 21142075
references.citation: Neurobiol Dis. 2011 Nov;44(2):248-58
references.pmid: 21784156
references.citation: J Biol Chem. 2003 Apr 4;278(14):11760-7
references.pmid: 12554736
references.citation: Hypertension. 2002 Jun;39(6):1058-63
references.pmid: 12052842
references.citation: IUBMB Life. 2000 May;49(5):405-9
references.pmid: 10902572
references.citation: Blood. 2010 Feb 25;115(8):1594-604
references.pmid: 19996089
references.citation: J Biol Chem. 1998 Aug 7;273(32):20308-16
references.pmid: 9685381
references.citation: Endocrine. 2003 Nov;22(2):135-42
references.pmid: 14665717
references.citation: J Biol Chem. 1994 Jan 14;269(2):1099-105
references.pmid: 8288567
references.citation: Annu Rev Physiol. 2007;69:451-82
references.pmid: 17037978
references.citation: J Biol Chem. 1998 May 15;273(20):12316-24
references.pmid: 9575184
references.citation: Biochemistry. 1991 May 28;30(21):5118-25
references.pmid: 1645191
references.citation: Nature. 2009 Jul 9;460(7252):278-82
references.pmid: 19506557
references.citation: EMBO J. 2009 Sep 16;28(18):2706-18
references.pmid: 19661922
references.citation: J Biol Chem. 2010 Mar 12;285(11):8316-29
references.pmid: 20056609
references.citation: Mol Cell Biol. 2004 Dec;24(23):10169-79
references.pmid: 15542828
references.citation: Biochem J. 2009 Dec 14;425(1):169-78
references.pmid: 19796012
references.citation: Int J Radiat Oncol Biol Phys. 2004;59(2 Suppl):21-6
references.pmid: 15142631
references.citation: J Cell Biol. 1982 Oct;95(1):316-22
references.pmid: 6982901
references.citation: Circulation. 1993 Feb;87(2):454-63
references.pmid: 8381058
references.citation: Front Biosci (Landmark Ed). 2011 Jun 01;16:3047-60
references.pmid: 21622221
references.citation: J Biol Chem. 1997 Jul 18;272(29):18273-80
references.pmid: 9218466
references.citation: Mol Biol Cell. 2005 Jul;16(7):3088-99
references.pmid: 15843435
references.citation: Pharmacol Ther. 2012 Jan;133(1):40-69
references.pmid: 21903131
references.citation: Biochemistry. 2011 Aug 16;50(32):6933-41
references.pmid: 21728385
references.citation: Mol Cancer Res. 2012 Jan;10(1):156-66
references.pmid: 22086906
references.citation: Nat Rev Mol Cell Biol. 2007 Jun;8(6):451-63
references.pmid: 17505520
references.citation: J Cell Biol. 2007 Jul 16;178(2):245-55
references.pmid: 17635935
references.citation: PLoS One. 2010 Mar 09;5(3):e9616
references.pmid: 20231902
references.citation: J Cell Biol. 2012 Apr 2;197(1):11-8
references.pmid: 22472437
references.citation: EMBO J. 2011 Jun 1;30(11):2233-45
references.pmid: 21522128
references.citation: J Clin Endocrinol Metab. 2002 Jul;87(7):3279-86
references.pmid: 12107237
references.citation: Cancer Res. 2010 Feb 1;70(3):1195-203
references.pmid: 20086174
references.citation: Neurobiol Aging. 2008 Mar;29(3):379-96
references.pmid: 17125886
references.citation: Exp Cell Res. 1984 Jul;153(1):109-20
references.pmid: 6376149
references.citation: Biochim Biophys Acta. 2005 Jun 30;1744(2):89-92
references.pmid: 15950749
references.citation: Mol Oral Microbiol. 2011 Aug;26(4):262-76
references.pmid: 21729247
references.citation: Neurobiol Aging. 2007 Dec;28(12):1873-88
references.pmid: 17011668
references.citation: J Biol Chem. 2002 Dec 13;277(50):48261-9
references.pmid: 12381737
references.citation: Methods Cell Biol. 1999;61:13-34
references.pmid: 9891307
references.citation: J Biol Chem. 2000 Aug 25;275(34):26515-22
references.pmid: 10852916
references.citation: J Biol Chem. 2000 Sep 22;275(38):29724-30
references.pmid: 10884381
references.citation: Eur Neuropsychopharmacol. 2010 Oct;20(10):721-30
references.pmid: 20493668
references.citation: Discov Med. 2011 Nov;12(66):419-32
references.pmid: 22127113
references.citation: J Pathol. 2008 Nov;216(3):317-27
references.pmid: 18767025
references.citation: Mol Cell. 2007 Sep 21;27(6):962-75
references.pmid: 17889669
references.citation: J Urol. 2012 Jan;187(1):322-9
references.pmid: 22099983
references.citation: J Biol Chem. 2012 May 18;287(21):17088-17099
references.pmid: 22467873
references.citation: Dev Cell. 2013 May 13;25(3):229-40
references.pmid: 23643362
references.citation: Mol Biol Cell. 2008 Jul;19(7):2973-83
references.pmid: 18463167
references.citation: Cell. 2008 Jun 13;133(6):1032-42
references.pmid: 18555779
references.citation: Cell Signal. 2012 Feb;24(2):468-475
references.pmid: 21983013
references.citation: J Clin Invest. 1997 May 1;99(9):2087-93
references.pmid: 9151780
references.citation: Cell Signal. 2009 May;21(5):675-84
references.pmid: 19211033
references.citation: Mol Biol Cell. 2012 Feb;23(3):401-11
references.pmid: 22130796
references.citation: Curr Biol. 2006 Oct 24;16(20):2042-7
references.pmid: 17055984
references.citation: J Cell Biol. 1982 May;93(2):507-12
references.pmid: 6980222
references.citation: J Biol Chem. 2010 Mar 5;285(10):7805-17
references.pmid: 20048153
references.citation: J Biol Chem. 2012 Feb 24;287(9):6928-40
references.pmid: 22223642