What is the first step in invadopodia assembly?2018-02-06T10:45:22+08:30

What is the first step in invadopodia assembly?

Initiation of invadopdia formation is highly complex, being influenced by various signalling cascades and phosphorylation events that occur following detection of a stimulant.

For example, activation of the epidermal growth factor (EGF) receptor by EGF has been shown to trigger and/or enhance invadopodia formation [1] as have platelet-derived growth factor (PDGF) and reactive oxygen species (ROS) (as reviewed in [2]). Following stimulation of the EGF receptor, the tyrosine kinase Src is activated, followed by the Abelson-related nonreceptor tyrosine kinase, Arg [3]. Src has traditionally been known as a vital component in the signaling cascade that governs the initiation of invadopodia formation [4][5][6][7] however more recent studies have also highlighted the importance of other Src family kinases [8] and protein kinase C [9] in this process.

Activation of these kinases are reported to increase the number of free actin barbed ends and lead to the phosphorylation of cortactin [10] and the scaffolding protein Tks5 (tyrosine kinase substrate with 5 SH3 domains) [7]. Together these events promote actin filament polymerization and maturation of the invadopodium [10]. Tks5 is also associated with the production of invadopodia in response to ROS [11].

In addition, the GTPase Cdc42 has been implicated in invadopodia formation via the regulation of neuronal Wiskott-Aldrich Syndrome protein (N-WASP), which acts in concert with the Arp2/3 complex to promote actin polymerization [9]. Similarly, cortactin is able to promote actin polymerization through binding and activating the Arp2/3 complex [12]. Live-cell imaging experiments have shown the accumulation of cortactin in invadopodia precedes matrix metalloproteinases (MMPs) accumulation and matrix degradation [5].

Ultimately the outcome of initiating invadopodia formation has been speculated to result in the production of a podosome-like precursor. This precursor structure comprises a small branched actin network, which is suggested to continue to polymerize and extend deeper into the extracellular matrix (ECM) [13] as MMPs are released from the tip of the elongating structure.

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  1. Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M, Segall J, Eddy R, Miki H, Takenawa T, and Condeelis J. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J. Cell Biol. 2005; 168(3):441-52. [PMID: 15684033]
  2. Murphy DA, and Courtneidge SA. The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function. Nat. Rev. Mol. Cell Biol. 2011; 12(7):413-26. [PMID: 21697900]
  3. Kimura F, Iwaya K, Kawaguchi T, Kaise H, Yamada K, Mukai K, Matsubara O, Ikeda N, and Kohno N. Epidermal growth factor-dependent enhancement of invasiveness of squamous cell carcinoma of the breast. Cancer Sci. 2010; 101(5):1133-40. [PMID: 20219074]
  4. Tarone G, Cirillo D, Giancotti FG, Comoglio PM, and Marchisio PC. Rous sarcoma virus-transformed fibroblasts adhere primarily at discrete protrusions of the ventral membrane called podosomes. Exp. Cell Res. 1985; 159(1):141-57. [PMID: 2411576]
  5. Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, and Mueller SC. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res. 2006; 66(6):3034-43. [PMID: 16540652]
  6. Kelley LC, Ammer AG, Hayes KE, Martin KH, Machida K, Jia L, Mayer BJ, and Weed SA. Oncogenic Src requires a wild-type counterpart to regulate invadopodia maturation. J. Cell. Sci. 2010; 123(Pt 22):3923-32. [PMID: 20980387]
  7. Stylli SS, Stacey TTI, Verhagen AM, Xu SS, Pass I, Courtneidge SA, and Lock P. Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. J. Cell. Sci. 2009; 122(Pt 15):2727-40. [PMID: 19596797]
  8. Ayala I, Baldassarre M, Giacchetti G, Caldieri G, Tetè S, Luini A, and Buccione R. Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation. J. Cell. Sci. 2008; 121(Pt 3):369-78. [PMID: 18198194]
  9. Mader CC, Oser M, Magalhaes MAO, Bravo-Cordero JJ, Condeelis J, Koleske AJ, and Gil-Henn H. An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res. 2011; 71(5):1730-41. [PMID: 21257711]
  10. Tehrani S, Tomasevic N, Weed S, Sakowicz R, and Cooper JA. Src phosphorylation of cortactin enhances actin assembly. Proc. Natl. Acad. Sci. U.S.A. 2007; 104(29):11933-8. [PMID: 17606906]
  11. Diaz B, Shani G, Pass I, Anderson D, Quintavalle M, and Courtneidge SA. Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation. Sci Signal 2009; 2(88):ra53. [PMID: 19755709]
  12. Uruno T, Liu J, Zhang P, Fan Yx , Egile C, Li R, Mueller SC, and Zhan X. Activation of Arp2/3 complex-mediated actin polymerization by cortactin. Nat. Cell Biol. 2001; 3(3):259-66. [PMID: 11231575]
  13. Linder S. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol. 2007; 17(3):107-17. [PMID: 17275303]