An EGFR-Src-Arg-Cortactin Pathway Mediates Functional Maturation of Invadopodia and Breast Cancer Cell Invasion

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.
Cancer Research (Impact Factor: 9.28). 02/2011; 71(5):1730-41. DOI: 10.1158/0008-5472.CAN-10-1432
Source: PubMed

ABSTRACT Invasive carcinoma cells use specialized actin polymerization-driven protrusions called invadopodia to degrade and possibly invade through the extracellular matrix (ECM) during metastasis. Phosphorylation of the invadopodium protein cortactin is a master switch that activates invadopodium maturation and function. Cortactin was originally identified as a hyperphosphorylated protein in v-Src-transformed cells, but the kinase or kinases that are directly responsible for cortactin phosphorylation in invadopodia remain unknown. In this study, we provide evidence that the Abl-related nonreceptor tyrosine kinase Arg mediates epidermal growth factor (EGF)-induced cortactin phosphorylation, triggering actin polymerization in invadopodia, ECM degradation, and matrix proteolysis-dependent tumor cell invasion. Both Src and Arg localize to invadopodia and are required for EGF-induced actin polymerization. Notably, Arg overexpression in Src knockdown cells can partially rescue actin polymerization in invadopodia while Src overexpression cannot compensate for loss of Arg, arguing that Src indirectly regulates invadopodium maturation through Arg activation. Our findings suggest a novel mechanism by which an EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Furthermore, they identify Arg as a novel mediator of invadopodia function and a candidate therapeutic target to inhibit tumor invasion in vivo.

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Available from: Marco Magalhaes, Dec 13, 2013
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    • "In terms of signal transduction, growth factor receptor tyrosine kinase and integrin initiated upstream events have been shown to promote invadopodia formation through phosphorylation of cortactin via a Src and Arg dependent pathway (Stylli et al., 2008; Oser et al., 2010; Destaing et al., 2011; Mader et al., 2011; MacGrath and Koleske, 2012). b1 integrin has been shown to promote metastasis, invadopodia maturation, and matrix degradation through Arg (Beaty et al., 2013). "
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    ABSTRACT: The leading cause of death in cancer patients is metastasis. Invasion is an integral part of metastasis and is carried out by proteolytic structures called invadopodia at the cellular level. In this introductory review, we start by evaluating the definition of invadopodia. While presenting the upstream signaling events involved, we integrate current models on invadopodia. In addition, we discuss the significance of invadopodia in 2D and 3D and in vivo. We finally point out technical challenges and conclude with open questions in the field.
    Turkish Journal of Biology 11/2014; 38(6):740-747. DOI:10.3906/biy-1404-110 · 1.34 Impact Factor
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    • "EGFR-Src-mediated phosphorylation of Arg Y439 on its activation loop then results in full Arg activation (Bradley and Koleske, 2009; Tanis et al., 2003). Arg phosphorylates cortactin on Y421 and Y466, which recruit Nck1, an adapter protein that binds N-WASp to facilitate Arp2/3 activation (Mader et al., 2011; Oser et al., 2010). This ultimately leads to synergistic cofilin-Arp2/3-dependent actin polymerization (Figure 2). "
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    ABSTRACT: Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for penetration through the basement membrane, stromal invasion and intravasation. Invadopodia are enriched in actin regulators, such as cortactin, cofilin, N-WASp, Arp2/3 and fascin. Much of the work to date has centered around identifying the proteins involved in regulating actin polymerization and matrix degradation. Recently, there have been significant advances in characterization of the very early stages of invadopodium precursor assembly and the role of adhesion proteins, such as β1 integrin, talin, FAK and Hic-5, in promoting invadopodium maturation. This review summarizes these findings in the context of our current model of invadopodial function and highlights some of the important unanswered questions in the field.
    European Journal of Cell Biology 10/2014; 93(10-12). DOI:10.1016/j.ejcb.2014.07.003 · 3.70 Impact Factor
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    • "We investigated the possibility that cyclin G2 might interact with cortactin and dynamin 2, actin-binding proteins and targets of oncogene src kinases [30], because they are well-defined regulators of actin dynamics and facilitators of ruffle formation, invadopodia formation , and consequent tumor invasion [31] [32] [33]. In glioblastoma cells, cyclin G2 co-localized with actin filaments and cortactin, or dynamin 2 at ruffles (Figure 4, A and B), and interacts with endogenous cortactin and dynamin 2 (Figure 4C ). "
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    ABSTRACT: Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton-associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma.
    Neoplasia (New York, N.Y.) 11/2013; 15(11):1272-81. DOI:10.1593/neo.131440 · 5.40 Impact Factor
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