title: Dense fibrillar collagen is a potent inducer of invadopodia via a specific signaling network.
abstract: Cell interactions with the extracellular matrix (ECM) can regulate multiple cellular activities and the matrix itself in dynamic, bidirectional processes. One such process is local proteolytic modification of the ECM. Invadopodia of tumor cells are actin-rich proteolytic protrusions that locally degrade matrix molecules and mediate invasion. We report that a novel high-density fibrillar collagen (HDFC) matrix is a potent inducer of invadopodia, both in carcinoma cell lines and in primary human fibroblasts. In carcinoma cells, HDFC matrix induced formation of invadopodia via a specific integrin signaling pathway that did not require growth factors or even altered gene and protein expression. In contrast, phosphoproteomics identified major changes in a complex phosphosignaling network with kindlin2 serine phosphorylation as a key regulatory element. This kindlin2-dependent signal transduction network was required for efficient induction of invadopodia on dense fibrillar collagen and for local degradation of collagen. This novel phosphosignaling mechanism regulates cell surface invadopodia via kindlin2 for local proteolytic remodeling of the ECM.
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School; and Department of Biostatistics, Bioinformatics, and Biomathematics; Georgetown University, Washington, DC 20057 vartym@mail.nih.gov kyamada@dir.nidcr.nih.gov.
authors: Vira V
authors: VV
authors: Artym
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892.
authors: Stephen
authors: S
authors: Swatkoski
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892.
authors: Kazue
authors: K
authors: Matsumoto
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892.
authors: Catherine B
authors: CB
authors: Campbell
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892.
authors: Ryan J
authors: RJ
authors: Petrie
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892.
authors: Emilios K
authors: EK
authors: Dimitriadis
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School; and Department of Biostatistics, Bioinformatics, and Biomathematics; Georgetown University, Washington, DC 20057.
authors: Xin
authors: X
authors: Li
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School; and Department of Biostatistics, Bioinformatics, and Biomathematics; Georgetown University, Washington, DC 20057.
authors: Susette C
authors: SC
authors: Mueller
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892.
authors: Thomas H
authors: TH
authors: Bugge
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892.
authors: Marjan
authors: M
authors: Gucek
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research; Proteomics Core Facility, National Heart, Lung, and Blood Institute; Biomolecular Engineering and Physical Sciences Shared Resource Program, National Institute of Biomolecular Imaging and Bioengineering; Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda, MD 20892 vartym@mail.nih.gov kyamada@dir.nidcr.nih.gov.
authors: Kenneth M
authors: KM
authors: Yamada
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000502:physiology*; D002645:Chickens; D024022:Fibrillar Collagens / Q000502:physiology*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: C477322:FERMT3 protein, human; D024022:Fibrillar Collagens; D038982:Integrin alpha2beta1; D008565:Membrane Proteins; D009363:Neoplasm Proteins
references: Clin Cancer Res. 1998 Feb;4(2):507-15
references: 9516943
references: Biophys J. 1998 May;74(5):2702-13
references: 9591694
references: J Pathol. 1998 Nov;186(3):262-8
references: 10211114
references: J Biol Chem. 1999 Aug 27;274(35):24947-52
references: 10455171
references: Science. 2009 Nov 27;326(5957):1216-9
references: 19965464
references: J Cell Biol. 2010 Jan 11;188(1):11-9
references: 19951899
references: Curr Biol. 2010 Feb 23;20(4):339-45
references: 20137952
references: Int J Biochem Cell Biol. 2010 May;42(5):595-603
references: 19854292
references: PLoS One. 2010;5(3):e9808
references: 20339555
references: Nat Cell Biol. 2013 Jun;15(6):625-36
references: 23708002
references: J Biol Chem. 2013 Jul 12;288(28):20248-60
references: 23720740
references: Methods Mol Biol. 2013;1046:171-89
references: 23868588
references: Prostate. 2013 Dec;73(16):1738-46
references: 24115186
references: Endocr Relat Cancer. 2013 Dec;20(6):R341-56
references: 24108109
references: Curr Biol. 2013 Nov 4;23(21):2079-89
references: 24206842
references: Cancer. 1999 Oct 1;86(7):1299-306
references: 10506717
references: Nat Biotechnol. 2005 Mar;23(3):355-60
references: 15696158
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W226-9
references: 15980458
references: Cancer Res. 2006 Mar 15;66(6):3034-43
references: 16540652
references: Genes Dev. 2006 Oct 1;20(19):2673-86
references: 16983145
references: Cell. 2006 Nov 3;127(3):635-48
references: 17081983
references: BMC Med. 2006;4(1):38
references: 17190588
references: J Cell Biol. 2010 May 3;189(3):541-56
references: 20421424
references: Curr Protoc Cell Biol. 2010 Sep;Chapter 10:Unit 10.18.1-20
references: 20853341
references: J Cell Sci. 2010 Nov 1;123(Pt 21):3662-73
references: 20971703
references: Nat Rev Cancer. 2010 Dec;10(12):858-70
references: 21102636
references: J Clin Invest. 2011 Jan;121(1):226-37
references: 21135504
references: Biophys J. 2011 Feb 2;100(3):573-82
references: 21281571
references: Dis Model Mech. 2011 Mar;4(2):165-78
references: 21324931
references: Wound Repair Regen. 2011 Mar-Apr;19(2):134-48
references: 21362080
references: J Cell Biol. 2011 Mar 7;192(5):883-97
references: 21357746
references: Sci Signal. 2011;4(164):rs3
references: 21406692
references: Curr Biol. 2011 Apr 26;21(8):635-44
references: 21474314
references: J Cell Sci. 2011 May 15;124(Pt 10):1739-51
references: 21525036
references: J Pathol. 2011 Jul;224(3):367-76
references: 21547905
references: Annu Rev Cell Dev Biol. 2011;27:321-45
references: 21663444
references: Annu Rev Cell Dev Biol. 2011;27:185-211
references: 21801014
references: PLoS One. 2011;6(10):e26858
references: 22046385
references: Biochem J. 2012 Jan 15;441(2):541-52
references: 22187935
references: J Cell Sci. 2011 Dec 1;124(Pt 23):3923-7
references: 22194302
references: Mol Biol Cell. 2012 Jan;23(2):297-309
references: 22114353
references: Am J Surg. 2012 Feb;203(2):222-9
references: 22056622
references: J Cell Sci. 2012 Feb 1;125(Pt 3):724-34
references: 22389406
references: J Cell Biol. 2012 Apr 30;197(3):439-55
references: 22547408
references: Cell Adh Migr. 2012 May-Jun;6(3):249-60
references: 22568982
references: Blood. 2013 Mar 28;121(13):2542-52
references: 23305739
references: Pancreas. 2013 May;42(4):663-9
references: 23508013
references: Clin Exp Metastasis. 2013 Jun;30(5):569-78
references: 23242739
references: Mol Biol Cell. 2013 Jun;24(11):1661-75, S1-11
references: 23552693
references: Dev Cell. 2013 May 28;25(4):402-16
references: 23685250
references: Cancer Res. 2007 May 1;67(9):4227-35
references: 17483334
references: Mol Cell Biol. 2007 Dec;27(23):8271-83
references: 17893324
references: Nat Cell Biol. 2007 Dec;9(12):1392-400
references: 18037882
references: Int J Cancer. 2008 Mar 1;122(5):1019-29
references: 17957794
references: BMC Med. 2008;6:11
references: 18442412
references: J Cell Sci. 2008 Jun 15;121(Pt 12):2054-61
references: 18505793
references: Endocr Relat Cancer. 2008 Sep;15(3):657-64
references: 18524948
references: Curr Biol. 2008 Sep 9;18(17):1295-9
references: 18718759
references: EMBO Rep. 2008 Dec;9(12):1203-8
references: 18997731
references: Mol Imaging. 2008 Sep-Oct;7(5):199-213
references: 19123990
references: Methods Mol Biol. 2009;522:211-9
references: 19247615
references: FEBS J. 2009 Mar;276(6):1610-28
references: 19220457
references: Sci Signal. 2009;2(84):ra46
references: 19690332
references: Sci Signal. 2009;2(87):ra51
references: 19738201
references: Sci Signal. 2009;2(88):ra53
references: 19755709
references: Trends Cell Biol. 2009 Oct;19(10):504-13
references: 19766491
references: Cell Signal. 2009 Dec;21(12):1961-73
references: 19755150
references: Cell. 2009 Nov 25;139(5):891-906
references: 19931152
references: Curr Biol. 2014 Jan 6;24(1):86-93
references: 24332539
references: PLoS One. 2014;9(1):e85485
references: 24427313
references: J Cell Biol. 2013 Dec 23;203(6):1063-79
references: 24344185
references: Curr Protoc Cell Biol. 2014;62:Unit 19.16.1-20
references: 24610123
references: Oncogene. 2014 May 8;33(19):2441-53
references: 23770848
references: Mol Biol Cell. 2014 Jul 1;25(13):2061-70
references: 24807903
references: Science. 2000 Oct 13;290(5490):333-7
references: 11030651
references: Science. 2001 Nov 23;294(5547):1708-12
references: 11721053
references: Nat Cell Biol. 2002 Apr;4(4):E65-8
references: 11944032
references: J Biomech Eng. 2002 Apr;124(2):214-22
references: 12002131
references: Cell. 2002 Sep 20;110(6):673-87
references: 12297042
references: Anal Chem. 2002 Oct 15;74(20):5383-92
references: 12403597
references: Cell. 2003 Apr 4;113(1):37-47
references: 12679033
references: J Biol Chem. 2003 May 16;278(20):18671-81
references: 12637511
references: Cancer Res. 2003 Aug 15;63(16):5028-33
references: 12941830
references: Anal Chem. 2003 Sep 1;75(17):4646-58
references: 14632076
references: Int J Cancer. 1977 Jul 15;20(1):1-5
references: 903179
references: J Theor Biol. 1982 Nov 7;99(1):31-68
references: 6892044
references: J Exp Zool. 1989 Aug;251(2):167-85
references: 2549171
references: Science. 1991 Mar 29;251(5001):1600-2
references: 2011740
references: Cancer. 1995 Feb 15;75(4):1010-7
references: 7842402
references: Cell. 1996 Nov 1;87(3):519-29
references: 8898204
references: J Biol Chem. 1996 Nov 1;271(44):27221-4
references: 8910291
references: Mol Biol Cell. 1997 Oct;8(10):1863-75
references: 9348529