title: Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation.
abstract: Invadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells. The mechanisms regulating invadopodium assembly and maturation are not understood. We have dissected the stages of invadopodium assembly and maturation and show that invadopodia use cortactin phosphorylation as a master switch during these processes. In particular, cortactin phosphorylation was found to regulate cofilin and Arp2/3 complex-dependent actin polymerization. Cortactin directly binds cofilin and inhibits its severing activity. Cortactin phosphorylation is required to release this inhibition so cofilin can sever actin filaments to create barbed ends at invadopodia to support Arp2/3-dependent actin polymerization. After barbed end formation, cortactin is dephosphorylated, which blocks cofilin severing activity thereby stabilizing invadopodia. These findings identify novel mechanisms for actin polymerization in the invadopodia of metastatic carcinoma cells and define four distinct stages of invadopodium assembly and maturation consisting of invadopodium precursor formation, actin polymerization, stabilization, and matrix degradation.
authors.affiliation: Department of Anatomy and Structural Biology and 2 Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA. moser@aecom.yu.edu
authors.forename: Matthew
authors.initials: M
authors.lastname: Oser
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Mader
authors.forename: J J
authors.initials: JJ
authors.lastname: Bravo-Cordero
authors.forename: Marianela
authors.initials: M
authors.lastname: Arias
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Chen
authors.forename: Vera
authors.initials: V
authors.lastname: Desmarais
authors.forename: Jacco
authors.initials: J
authors.lastname: van Rheenen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D051356:Cortactin; C078332:Nck protein; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D014443:Tyrosine; D004815:Epidermal Growth Factor; D015688:Oncogene Protein pp60(v-src); D053511:Matrix Metalloproteinase 14
references.citation: Mol Biol Cell. 2003 Aug;14(8):3216-29
references.pmid: 12925758
references.citation: EMBO J. 2007 Mar 21;26(6):1499-510
references.pmid: 17332756
references.citation: J Cell Biol. 2008 Jul 14;182(1):157-69
references.pmid: 18606851
references.citation: J Cell Biol. 2005 Aug 15;170(4):637-48
references.pmid: 16087707
references.citation: J Cell Biol. 2007 Dec 17;179(6):1247-59
references.pmid: 18086920
references.citation: J Cell Sci. 2005 Feb 15;118(Pt 4):807-17
references.pmid: 15671060
references.citation: Cold Spring Harb Symp Quant Biol. 2005;70:167-71
references.pmid: 16869750
references.citation: Mol Cell Biol. 2004 Jun;24(12):5269-80
references.pmid: 15169891
references.citation: Cell Motil Cytoskeleton. 2004 Apr;57(4):207-17
references.pmid: 14752805
references.citation: J Biol Chem. 2005 Feb 18;280(7):5836-42
references.pmid: 15579908
references.citation: J Cell Sci. 2008 Feb 1;121(Pt 3):369-78
references.pmid: 18198194
references.citation: Curr Biol. 2005 Jul 26;15(14):1276-85
references.pmid: 16051170
references.citation: Biochim Biophys Acta. 2007 May;1773(5):642-52
references.pmid: 16926057
references.citation: J Neurosci. 2003 Dec 17;23(37):11759-69
references.pmid: 14684878
references.citation: Curr Biol. 2002 Jan 8;12(1):79-84
references.pmid: 11790308
references.citation: Cell Motil Cytoskeleton. 2009 Jun;66(6):303-16
references.pmid: 19373774
references.citation: Curr Biol. 2001 Mar 6;11(5):370-4
references.pmid: 11267876
references.citation: Curr Biol. 1999 Oct 7;9(19):1127-30
references.pmid: 10531012
references.citation: J Cell Biol. 2004 Mar 15;164(6):899-910
references.pmid: 15024035
references.citation: Cancer Cell. 2005 Feb;7(2):155-65
references.pmid: 15710328
references.citation: Trends Cell Biol. 2001 Jul;11(7):288-93
references.pmid: 11413039
references.citation: Dev Cell. 2008 Dec;15(6):813-28
references.pmid: 19081071
references.citation: Curr Biol. 2004 Apr 20;14(8):697-703
references.pmid: 15084285
references.citation: Curr Opin Cell Biol. 2008 Apr;20(2):235-41
references.pmid: 18337078
references.citation: Int J Biochem Cell Biol. 2006;38(11):1875-92
references.pmid: 16790362
references.citation: J Cell Sci. 2004 Jul 15;117(Pt 16):3499-510
references.pmid: 15252126
references.citation: Cancer Res. 2006 Mar 15;66(6):3034-43
references.pmid: 16540652
references.citation: Trends Cell Biol. 2007 Mar;17(3):107-17
references.pmid: 17275303
references.citation: J Cell Sci. 2000 Apr;113 ( Pt 7):1287-98
references.pmid: 10704379
references.citation: J Cell Biol. 2005 Jan 31;168(3):441-52
references.pmid: 15684033
references.citation: Nat Cell Biol. 2001 Mar;3(3):259-66
references.pmid: 11231575
references.citation: J Cell Sci. 1998 Jan;111 ( Pt 2):199-211
references.pmid: 9405304
references.citation: Curr Biol. 2006 Aug 8;16(15):1515-23
references.pmid: 16890527
references.citation: Curr Biol. 2007 Mar 6;17(5):445-51
references.pmid: 17306540
references.citation: Am J Physiol Cell Physiol. 2006 Feb;290(2):C463-71
references.pmid: 16162656
references.citation: J Cell Biol. 2000 Oct 2;151(1):29-40
references.pmid: 11018051
references.citation: J Cell Biol. 2008 Mar 24;180(6):1245-60
references.pmid: 18362183
references.citation: J Biol Chem. 2008 Jun 6;283(23):15740-6
references.pmid: 18387954
references.citation: J Exp Zool. 1989 Aug;251(2):167-85
references.pmid: 2549171
references.citation: Biophys J. 2004 Apr;86(4):2517-29
references.pmid: 15041688
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11933-8
references.pmid: 17606906
references.citation: J Cell Biol. 2009 Apr 20;185(2):357-70
references.pmid: 19364917
references.citation: Mol Biol Cell. 2009 Feb;20(3):948-62
references.pmid: 19109420
references.citation: J Cell Biol. 2008 Mar 10;180(5):957-71
references.pmid: 18332219
references.citation: J Cell Biol. 2007 Nov 19;179(4):777-91
references.pmid: 18025308
references.citation: Cancer Res. 2007 May 1;67(9):4227-35
references.pmid: 17483334
references.citation: J Cell Biol. 2004 Aug 30;166(5):697-708
references.pmid: 15337778
references.citation: Science. 2004 Apr 30;304(5671):743-6
references.pmid: 15118165
references.citation: Curr Biol. 2002 Aug 6;12(15):1270-8
references.pmid: 12176354