Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation.
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.
Oser
Matthew
M
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
Yamaguchi
Hideki
H
Mader
Christopher C
CC
Bravo-Cordero
J J
JJ
Arias
Marianela
M
Chen
Xiaoming
X
Desmarais
Vera
V
van Rheenen
Jacco
J
Koleske
Anthony J
AJ
Condeelis
John
J
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*
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
Mol Biol Cell. 2003 Aug;14(8):3216-29
12925758
EMBO J. 2007 Mar 21;26(6):1499-510
17332756
J Cell Biol. 2008 Jul 14;182(1):157-69
18606851
J Cell Biol. 2005 Aug 15;170(4):637-48
16087707
J Cell Biol. 2007 Dec 17;179(6):1247-59
18086920
J Cell Sci. 2005 Feb 15;118(Pt 4):807-17
15671060
Cold Spring Harb Symp Quant Biol. 2005;70:167-71
16869750
Mol Cell Biol. 2004 Jun;24(12):5269-80
15169891
Cell Motil Cytoskeleton. 2004 Apr;57(4):207-17
14752805
J Biol Chem. 2005 Feb 18;280(7):5836-42
15579908
J Cell Sci. 2008 Feb 1;121(Pt 3):369-78
18198194
Curr Biol. 2005 Jul 26;15(14):1276-85
16051170
Biochim Biophys Acta. 2007 May;1773(5):642-52
16926057
J Neurosci. 2003 Dec 17;23(37):11759-69
14684878
Curr Biol. 2002 Jan 8;12(1):79-84
11790308
Cell Motil Cytoskeleton. 2009 Jun;66(6):303-16
19373774
Curr Biol. 2001 Mar 6;11(5):370-4
11267876
Curr Biol. 1999 Oct 7;9(19):1127-30
10531012
J Cell Biol. 2004 Mar 15;164(6):899-910
15024035
Cancer Cell. 2005 Feb;7(2):155-65
15710328
Trends Cell Biol. 2001 Jul;11(7):288-93
11413039
Dev Cell. 2008 Dec;15(6):813-28
19081071
Curr Biol. 2004 Apr 20;14(8):697-703
15084285
Curr Opin Cell Biol. 2008 Apr;20(2):235-41
18337078
Int J Biochem Cell Biol. 2006;38(11):1875-92
16790362
J Cell Sci. 2004 Jul 15;117(Pt 16):3499-510
15252126
Cancer Res. 2006 Mar 15;66(6):3034-43
16540652
Trends Cell Biol. 2007 Mar;17(3):107-17
17275303
J Cell Sci. 2000 Apr;113 ( Pt 7):1287-98
10704379
J Cell Biol. 2005 Jan 31;168(3):441-52
15684033
Nat Cell Biol. 2001 Mar;3(3):259-66
11231575
J Cell Sci. 1998 Jan;111 ( Pt 2):199-211
9405304
Curr Biol. 2006 Aug 8;16(15):1515-23
16890527
Curr Biol. 2007 Mar 6;17(5):445-51
17306540
Am J Physiol Cell Physiol. 2006 Feb;290(2):C463-71
16162656
J Cell Biol. 2000 Oct 2;151(1):29-40
11018051
J Cell Biol. 2008 Mar 24;180(6):1245-60
18362183
J Biol Chem. 2008 Jun 6;283(23):15740-6
18387954
J Exp Zool. 1989 Aug;251(2):167-85
2549171
Biophys J. 2004 Apr;86(4):2517-29
15041688
Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11933-8
17606906
J Cell Biol. 2009 Apr 20;185(2):357-70
19364917
Mol Biol Cell. 2009 Feb;20(3):948-62
19109420
J Cell Biol. 2008 Mar 10;180(5):957-71
18332219
J Cell Biol. 2007 Nov 19;179(4):777-91
18025308
Cancer Res. 2007 May 1;67(9):4227-35
17483334
J Cell Biol. 2004 Aug 30;166(5):697-708
15337778
Science. 2004 Apr 30;304(5671):743-6
15118165
Curr Biol. 2002 Aug 6;12(15):1270-8
12176354