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PMID: 19364917 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

FAK alters invadopodia and focal adhesion composition and dynamics to regulate breast cancer invasion.

The Journal of cell biology ·Vol. 185 ·No. 2 ·2009-04-20 ·Pages 357-70

Chan KT, Cortesio CL, Huttenlocher A

Abstract

Focal adhesion kinase (FAK) is important for breast cancer progression and invasion and is necessary for the dynamic turnover of focal adhesions. However, it has not been determined whether FAK also regulates the dynamics of invasive adhesions formed in cancer cells known as invadopodia. In this study, we report that endogenous FAK functions upstream of cellular Src (c-Src) as a negative regulator of invadopodia formation and dynamics in breast cancer cells. We show that depletion of FAK induces the formation of active invadopodia but impairs invasive cell migration. FAK-deficient MTLn3 breast cancer cells display enhanced assembly and dynamics of invadopodia that are rescued by expression of wild-type FAK but not by FAK that cannot be phosphorylated at tyrosine 397. Moreover, our findings demonstrate that FAK depletion switches phosphotyrosine-containing proteins from focal adhesions to invadopodia through the temporal and spatial regulation of c-Src activity. Collectively, our findings provide novel insight into the interplay between FAK and Src to promote invasion.

MeSH Terms
Breast Neoplasms/metabolism,pathology Cell Line, Tumor Cell Movement/physiology Cell Surface Extensions/metabolism Female Focal Adhesion Protein-Tyrosine Kinases/genetics,metabolism Focal Adhesions/metabolism Humans Neoplasm Invasiveness Paxillin/genetics,metabolism RNA, Small Interfering/genetics,metabolism Recombinant Fusion Proteins/genetics,metabolism Tyrosine/metabolism src-Family Kinases/metabolism
Chemicals
Paxillin RNA, Small Interfering Recombinant Fusion Proteins Tyrosine Focal Adhesion Protein-Tyrosine Kinases src-Family Kinases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Chan Keefe T
Department of Molecular and Cellular Pharmacology, University of Wisconsin, Madison, WI 53706, USA.
Cortesio Christa L
Huttenlocher Anna
References (54)
54 references, click to expand
  1. Foot and mouth: podosomes, invadopodia and circular dorsal ruffles.
    Nat Rev Mol Cell Biol. 2004 Aug;5(8):647-57 PMID: 15366708
  2. Proteolysis of cortactin by calpain regulates membrane protrusion during cell migration.
    Mol Biol Cell. 2006 Jan;17(1):239-50 PMID: 16280362
  3. Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model.
    Oncogene. 2006 Jul 27;25(32):4429-40 PMID: 16547501
  4. EGF stimulates lamellipod extension in metastatic mammary adenocarcinoma cells by an actin-dependent mechanism.
    Clin Exp Metastasis. 1996 Jan;14(1):61-72 PMID: 8521618
  5. Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation.
    Cancer Res. 2005 Jun 1;65(11):4698-706 PMID: 15930288
  6. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes.
    Clin Cancer Res. 2000 Jun;6(6):2417-23 PMID: 10873094
  7. Ultrastructure and gold-immunolabelling of cell-substratum adhesions (podosomes) in RSV-transformed BHK cells.
    J Cell Sci. 1989 Sep;94 ( Pt 1):85-99 PMID: 2482298
  8. Focal adhesion and actin dynamics: a place where kinases and proteases meet to promote invasion.
    Trends Cell Biol. 2004 May;14(5):241-9 PMID: 15130580
  9. Differential regulation of cell motility and invasion by FAK.
    J Cell Biol. 2003 Mar 3;160(5):753-67 PMID: 12615911
  10. Fibronectin: purification, immunochemical properties, and biological activities.
    Methods Enzymol. 1982;82 Pt A:803-31 PMID: 7078457
  11. Calpain-mediated proteolysis of talin regulates adhesion dynamics.
    Nat Cell Biol. 2004 Oct;6(10):977-83 PMID: 15448700
  12. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src.
    Mol Cell Biol. 1994 Mar;14(3):1680-8 PMID: 7509446
  13. Bidirectional signaling between the cytoskeleton and integrins.
    Curr Opin Cell Biol. 1999 Apr;11(2):274-86 PMID: 10209151
  14. Tyrosine phosphorylation of Crk-associated substrates by focal adhesion kinase. A putative mechanism for the integrin-mediated tyrosine phosphorylation of Crk-associated substrates.
    J Biol Chem. 1997 Nov 14;272(46):29083-90 PMID: 9360983
  15. Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix.
    Cancer Metastasis Rev. 2009 Jun;28(1-2):137-49 PMID: 19153671
  16. Specialized surface protrusions of invasive cells, invadopodia and lamellipodia, have differential MT1-MMP, MMP-2, and TIMP-2 localization.
    Ann N Y Acad Sci. 1999 Jun 30;878:361-71 PMID: 10415741
  17. Focal adhesion kinase: in command and control of cell motility.
    Nat Rev Mol Cell Biol. 2005 Jan;6(1):56-68 PMID: 15688067
  18. Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells.
    Mol Cancer Res. 2005 Jun;3(6):307-15 PMID: 15972849
  19. Podosomes: adhesion hot-spots of invasive cells.
    Trends Cell Biol. 2003 Jul;13(7):376-85 PMID: 12837608
  20. A dynamic podosome-like structure of epithelial cells.
    Exp Cell Res. 2004 May 1;295(2):360-74 PMID: 15093736
  21. Sequential signals toward podosome formation in NIH-src cells.
    J Cell Biol. 2008 Jul 14;182(1):157-69 PMID: 18606851
  22. Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas.
    Nat Genet. 1998 Aug;19(4):361-5 PMID: 9697697
  23. Focal adhesion kinase modulates tension signaling to control actin and focal adhesion dynamics.
    J Cell Biol. 2007 Feb 26;176(5):667-80 PMID: 17325207
  24. Tyrosine phosphorylation and cytoskeletal tension regulate the release of fibroblast adhesions.
    J Cell Biol. 1995 Oct;131(2):525-37 PMID: 7593176
  25. Focal adhesion kinase is required for the spatial organization of the leading edge in migrating cells.
    J Cell Sci. 2005 Jun 15;118(Pt 12):2613-23 PMID: 15914540
  26. Molecular diversity of cell-matrix adhesions.
    J Cell Sci. 1999 Jun;112 ( Pt 11):1655-69 PMID: 10318759
  27. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20302-7 PMID: 18056629
  28. Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors.
    Cancer Res. 1995 Jul 1;55(13):2752-5 PMID: 7796399
  29. Invadopodia and podosomes in tumor invasion.
    Eur J Cell Biol. 2006 Apr;85(3-4):213-8 PMID: 16546563
  30. Differential dynamics of alpha 5 integrin, paxillin, and alpha-actinin during formation and disassembly of adhesions in migrating cells.
    J Cell Biol. 2001 Jun 25;153(7):1427-40 PMID: 11425873
  31. Characterization of tyrosine phosphorylation of paxillin in vitro by focal adhesion kinase.
    J Biol Chem. 1995 Jul 21;270(29):17437-41 PMID: 7615549
  32. Complex formation with focal adhesion kinase: A mechanism to regulate activity and subcellular localization of Src kinases.
    Mol Biol Cell. 1999 Oct;10(10):3489-505 PMID: 10512882
  33. FAK integrates growth-factor and integrin signals to promote cell migration.
    Nat Cell Biol. 2000 May;2(5):249-56 PMID: 10806474
  34. Live-cell monitoring of tyrosine phosphorylation in focal adhesions following microtubule disruption.
    J Cell Sci. 2003 Mar 15;116(Pt 6):975-86 PMID: 12584242
  35. The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells.
    Cancer Cell. 2005 Feb;7(2):155-65 PMID: 15710328
  36. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration.
    J Cell Sci. 1999 Aug;112 ( Pt 16):2677-91 PMID: 10413676
  37. High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype.
    Mod Pathol. 2005 Oct;18(10):1289-94 PMID: 15861214
  38. FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly.
    Nat Cell Biol. 2004 Feb;6(2):154-61 PMID: 14743221
  39. PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility.
    J Cell Biol. 2008 Jan 14;180(1):187-203 PMID: 18195107
  40. Co-localization of cortactin and phosphotyrosine identifies active invadopodia in human breast cancer cells.
    Exp Cell Res. 2006 May 1;312(8):1240-53 PMID: 16442522
  41. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function.
    Cancer Res. 2006 Mar 15;66(6):3034-43 PMID: 16540652
  42. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation.
    Trends Cell Biol. 2007 Mar;17(3):107-17 PMID: 17275303
  43. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin.
    J Cell Biol. 2005 Jan 31;168(3):441-52 PMID: 15684033
  44. v-Src SH3-enhanced interaction with focal adhesion kinase at beta 1 integrin-containing invadopodia promotes cell invasion.
    J Biol Chem. 2002 Apr 12;277(15):12487-90 PMID: 11839732
  45. Focal adhesion kinase is not required for Src-induced formation of invadopodia in KM12C colon cancer cells and can interfere with their assembly.
    Eur J Cell Biol. 2008 Sep;87(8-9):569-79 PMID: 18562041
  46. FAK signaling is critical for ErbB-2/ErbB-3 receptor cooperation for oncogenic transformation and invasion.
    J Cell Biol. 2005 Nov 7;171(3):505-16 PMID: 16275754
  47. Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer cell invasion.
    J Cell Biol. 2008 Mar 10;180(5):957-71 PMID: 18332219
  48. FAK regulates biological processes important for the pathogenesis of cancer.
    Cancer Metastasis Rev. 2003 Dec;22(4):359-74 PMID: 12884911
  49. Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia.
    Cancer Res. 2007 May 1;67(9):4227-35 PMID: 17483334
  50. Molecular mechanisms of cancer cell invasion and plasticity.
    Br J Dermatol. 2006 May;154 Suppl 1:11-5 PMID: 16712711
  51. Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase.
    Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10148-52 PMID: 7937853
  52. Focal adhesion kinase promotes phospholipase C-gamma1 activity.
    Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9021-6 PMID: 10430888
  53. Global impact of oncogenic Src on a phosphotyrosine proteome.
    J Proteome Res. 2008 Aug;7(8):3447-60 PMID: 18563927
  54. Inhibition of calpain stabilises podosomes and impairs dendritic cell motility.
    J Cell Sci. 2006 Jun 1;119(Pt 11):2375-85 PMID: 16723743
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200809110
Published
2009-04-20
Epub
2009-00-13
Pages
357-70
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2700377
Subset
IM
Grants
NCI NIH HHS · R01 CA085862 · United States
NCI NIH HHS · R01 CA085862-08 · United States
External Links
PubMed source DOI: 10.1083/jcb.200809110 PMC Full Text View journal details
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