title: Polarity-regulating kinase partitioning-defective 1b (PAR1b) phosphorylates guanine nucleotide exchange factor H1 (GEF-H1) to regulate RhoA-dependent actin cytoskeletal reorganization.
abstract: Partitioning-defective 1b (PAR1b), also known as microtubule affinity-regulating kinase 2 (MARK2), is a member of evolutionally conserved PAR1/MARK serine/threonine kinase family, which plays a key role in the establishment and maintenance of cell polarity at least partly by phosphorylating microtubule-associated proteins (MAPs) that regulate microtubule stability. PAR1b has also been reported to influence actin cytoskeletal organization, raising the possibility that PAR1b functionally interacts with the Rho family of small GTPases, central regulators of the actin cytoskeletal system. Consistent with this notion, PAR1 was recently found to be physically associated with a RhoA-specific guanine nucleotide exchange factor H1 (GEF-H1). This observation suggests a functional link between PAR1b and GEF-H1. Here we show that PAR1b induces phosphorylation of GEF-H1 on serine 885 and serine 959. We also show that PAR1b-induced serine 885/serine 959 phosphorylation inhibits RhoA-specific GEF activity of GEF-H1. As a consequence, GEF-H1 phosphorylated on both of the serine residues loses the ability to stimulate RhoA and thereby fails to induce RhoA-dependent stress fiber formation. These findings indicate that PAR1b not only regulates microtubule stability through phosphorylation of MAPs but also influences actin stress fiber formation by inducing GEF-H1 phosphorylation. The dual function of PAR1b in the microtubule-based cytoskeletal system and the actin-based cytoskeletal system in the coordinated regulation of cell polarity, cell morphology, and cell movement.
authors.affiliation: Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yamahashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Naoko
authors.initials: N
authors.lastname: Murata-Kamiya
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D002522:Chlorocebus aethiops; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C577356:ARHGEF2 protein, human; D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020742:rhoA GTP-Binding Protein
references.citation: Cell. 1997 Apr 18;89(2):297-308
references.pmid: 9108484
references.citation: Cell. 2003 Dec 12;115(6):691-704
references.pmid: 14675534
references.citation: Trends Cell Biol. 2008 May;18(5):210-9
references.pmid: 18394899
references.citation: Cell. 1992 Aug 7;70(3):389-99
references.pmid: 1643657
references.citation: Dev Cell. 2007 May;12(5):699-712
references.pmid: 17488622
references.citation: Nat Cell Biol. 2002 Apr;4(4):294-301
references.pmid: 11912491
references.citation: J Cell Sci. 2006 Mar 15;119(Pt 6):979-87
references.pmid: 16525119
references.citation: Nature. 2007 May 17;447(7142):330-3
references.pmid: 17507984
references.citation: Annu Rev Biophys. 2010;39:449-70
references.pmid: 20192778
references.citation: Cell. 2004 Jan 23;116(2):167-79
references.pmid: 14744429
references.citation: Cell. 1988 Feb 12;52(3):311-20
references.pmid: 3345562
references.citation: Infect Immun. 2007 Mar;75(3):1203-13
references.pmid: 17194805
references.citation: J Biol Chem. 2004 Mar 26;279(13):12804-11
references.pmid: 14676191
references.citation: J Biol Chem. 2004 Apr 30;279(18):18392-400
references.pmid: 14970201
references.citation: Dev Cell. 2007 Nov;13(5):609-622
references.pmid: 17981131
references.citation: Proteomics. 2004 Jun;4(6):1551-61
references.pmid: 15174125
references.citation: J Biol Chem. 2009 Aug 21;284(34):23024-36
references.pmid: 19553659
references.citation: Methods Enzymol. 2006;406:425-37
references.pmid: 16472675
references.citation: Curr Opin Cell Biol. 1997 Feb;9(1):86-92
references.pmid: 9013670
references.citation: Cell. 1992 Aug 7;70(3):401-10
references.pmid: 1643658
references.citation: J Cell Sci. 2007 Oct 15;120(Pt 20):3491-9
references.pmid: 17928305
references.citation: Curr Opin Cell Biol. 2003 Feb;15(1):67-72
references.pmid: 12517706
references.citation: Nature. 2006 Apr 20;440(7087):1069-72
references.pmid: 16547516
references.citation: Biochem Biophys Res Commun. 2011 May 6;408(2):322-8
references.pmid: 21513698
references.citation: Annu Rev Cell Dev Biol. 2005;21:247-69
references.pmid: 16212495
references.citation: J Cell Biol. 2005 Jul 18;170(2):295-304
references.pmid: 16009721
references.citation: Curr Biol. 2004 Aug 24;14(16):1425-35
references.pmid: 15324659
references.citation: Biochem Biophys Res Commun. 2008 Mar 28;368(1):162-7
references.pmid: 18211802
references.citation: J Exp Med. 2010 Sep 27;207(10):2157-74
references.pmid: 20855497
references.citation: Cell Motil Cytoskeleton. 1999 Nov;44(3):209-24
references.pmid: 10542369
references.citation: Science. 2002 Jan 25;295(5555):683-6
references.pmid: 11743164
references.citation: Development. 1996 Oct;122(10):3133-40
references.pmid: 8898226
references.citation: Curr Biol. 2004 Apr 20;14(8):736-41
references.pmid: 15084291
references.citation: Cold Spring Harb Perspect Biol. 2009 Aug;1(2):a001370
references.pmid: 20066082
references.citation: Sci STKE. 2005 Aug 09;2005(296):re10
references.pmid: 16091624
references.citation: Dev Cell. 2005 May;8(5):777-86
references.pmid: 15866167
references.citation: Trends Cell Biol. 2006 Oct;16(10):522-9
references.pmid: 16949823