title: Rac1 and Cdc42 differentially modulate cigarette smoke-induced airway cell migration through p120-catenin-dependent and -independent pathways.
abstract: The adherens junction protein p120-catenin (p120ctn) shuttles between E-cadherin-bound and cytoplasmic pools to regulate E-cadherin/catenin complex stability and cell migration, respectively. When released from the adherens junction, p120ctn promotes cell migration through modulation of the Rho GTPases Rac1, Cdc42, and RhoA. Accordingly, the down-regulation and cytoplasmic mislocalization of p120ctn has been reported in all subtypes of lung cancers and is associated with grave prognosis. Previously, we reported that cigarette smoke induced cytoplasmic translocation of p120ctn and cell migration, but the underlying mechanism was unclear. Using primary human bronchial epithelial cells exposed to smoke-concentrated medium (Smk), we observed the translocation of Rac1 and Cdc42, but not RhoA, to the leading edge of polarized and migrating human bronchial epithelial cells. Rac1 and Cdc42 were robustly activated by smoke, whereas RhoA was inhibited. Accordingly, siRNA knockdown of Rac1 or Cdc42 completely abolished Smk-induced cell migration, whereas knockdown of RhoA had no effect. p120ctn/Rac1 double knockdown completely abolished Smk-induced cell migration, whereas p120ctn/Cdc42 double knockdown did not. These data suggested that Rac1 and Cdc42 coactivation was essential to smoke-promoted cell migration in the presence of p120ctn, whereas migration proceeded via Rac1 alone in the absence of p120ctn. Thus, Rac1 may provide an omnipotent therapeutic target in reversing cell migration during the early (intact p120ctn) and late (loss of p120ctn) stages of lung carcinogenesis.
authors.affiliation: Francis I. Proctor Foundation, San Francisco, California, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.forename: Lorna
authors.initials: L
authors.lastname: Zlock
authors.forename: Walter E
authors.initials: WE
authors.lastname: Finkbeiner
authors.forename: Nancy A
authors.initials: NA
authors.lastname: McNamara
mesh_terms: D001980:Bronchi / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051177:Catenins / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D012906:Smoke; D014026:Nicotiana; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D017077:Culture Media, Conditioned; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D012906:Smoke; C066737:RHOA protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin
references.citation: Genes Cells. 1996 Jan;1(1):73-86
references.pmid: 9078368
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Oncogene. 2004 Oct 18;23(48):7947-56
references.pmid: 15489912
references.citation: J Cell Sci. 2001 Feb;114(Pt 4):695-707
references.pmid: 11171375
references.citation: J Cell Biol. 1999 Nov 29;147(5):1009-22
references.pmid: 10579721
references.citation: Am J Pathol. 2010 Sep;177(3):1255-64
references.pmid: 20651243
references.citation: Lung Cancer. 2009 Mar;63(3):375-82
references.pmid: 19162367
references.citation: J Cell Biol. 2011 Mar 21;192(6):907-17
references.pmid: 21422226
references.citation: J Clin Oncol. 2003 Mar 1;21(5):921-6
references.pmid: 12610194
references.citation: Cell. 2006 Dec 1;127(5):1027-39
references.pmid: 17129786
references.citation: Curr Opin Cell Biol. 2001 Oct;13(5):604-10
references.pmid: 11544030
references.citation: Cancer Res. 2005 Jun 15;65(12):5076-83
references.pmid: 15958551
references.citation: Clin Lung Cancer. 2004 May;5(6):371-6
references.pmid: 15217537
references.citation: Am J Respir Cell Mol Biol. 2006 Jul;35(1):3-9
references.pmid: 16484682
references.citation: Nat Cell Biol. 2000 Sep;2(9):637-44
references.pmid: 10980705
references.citation: J Cell Biol. 2003 Nov 10;163(3):525-34
references.pmid: 14610055
references.citation: Semin Respir Crit Care Med. 2011 Feb;32(1):32-43
references.pmid: 21500122
references.citation: Biochem Biophys Res Commun. 2012 Jan 6;417(1):49-55
references.pmid: 22120634
references.citation: J Cell Sci. 2008 Aug 15;121(Pt 16):2635-42
references.pmid: 18653540
references.citation: PLoS One. 2006 Dec 20;1:e93
references.pmid: 17183725
references.citation: Curr Biol. 1995 Apr 1;5(4):393-403
references.pmid: 7627555
references.citation: J Pathol. 2013 Jan;229(1):74-86
references.pmid: 22833523
references.citation: Nat Rev Cancer. 2009 Jul;9(7):476-88
references.pmid: 19550424
references.citation: Cell. 2010 Apr 2;141(1):117-28
references.pmid: 20371349
references.citation: J Cell Sci. 1995 Jan;108 ( Pt 1):225-33
references.pmid: 7738099
references.citation: IARC Monogr Eval Carcinog Risks Hum. 2004;83:1-1438
references.pmid: 15285078
references.citation: Cell. 1995 Apr 7;81(1):53-62
references.pmid: 7536630
references.citation: Differentiation. 2002 Dec;70(9-10):583-9
references.pmid: 12492499
references.citation: Cancer Res. 2008 Oct 15;68(20):8473-81
references.pmid: 18922921
references.citation: J Cell Biol. 2000 Aug 7;150(3):567-80
references.pmid: 10931868
references.citation: Science. 1999 Aug 6;285(5429):895-8
references.pmid: 10436159
references.citation: Annu Rev Cell Dev Biol. 1999;15:185-230
references.pmid: 10611961
references.citation: Nat Cell Biol. 2006 Aug;8(8):781-2
references.pmid: 16880807
references.citation: Cell. 2004 Jan 23;116(2):167-79
references.pmid: 14744429
references.citation: Am J Respir Cell Mol Biol. 1994 Sep;11(3):312-20
references.pmid: 8086168
references.citation: J Clin Oncol. 2010 Oct 20;28(30):4616-20
references.pmid: 20855837
references.citation: Nat Cell Biol. 2003 Mar;5(3):236-41
references.pmid: 12598902
references.citation: J Cell Biol. 2008 Nov 17;183(4):737-49
references.pmid: 19015320
references.citation: Mol Cell Biol. 2001 Oct;21(20):6796-807
references.pmid: 11564864
references.citation: Cancer Res. 2007 Sep 15;67(18):8966-72
references.pmid: 17875740
references.citation: Cancer Sci. 2009 Mar;100(3):441-8
references.pmid: 19154401
references.citation: Mol Biol Cell. 2004 Mar;15(3):1003-10
references.pmid: 14699061
references.citation: Cancer Epidemiol Biomarkers Prev. 2012 Jun;21(6):988-92
references.pmid: 22523180
references.citation: Nat Cell Biol. 1999 Sep;1(5):253-9
references.pmid: 10559936
references.citation: Oncogene. 2012 Nov 8;31(45):4768-77
references.pmid: 22249257
references.citation: J Cell Biol. 2009 Oct 5;187(1):119-33
references.pmid: 19805632
references.citation: J Cell Sci. 2006 Feb 15;119(Pt 4):769-81
references.pmid: 16449321
references.citation: Nat Rev Cancer. 2009 Apr;9(4):265-73
references.pmid: 19262571
references.citation: Am J Physiol. 1992 Jun;262(6 Pt 1):L713-24
references.pmid: 1616056
references.citation: Science. 2004 Apr 30;304(5671):743-6
references.pmid: 15118165
references.citation: Mol Cancer Ther. 2009 Jun;8(6):1557-69
references.pmid: 19509242