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: 9.33). 02/2011; 71(5):1730-41. DOI: 10.1158/0008-5472.CAN-10-1432
Source: PubMed


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 · 3.83 Impact Factor
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    • "Accumulating evidence in other cancer cells indicates that Abl2 could phosphorylate protein cortactin, a master switch that activates invadopodium maturation and function, which in turn promotes cancerous matrix degradation and invasive cancer cells migration.14,15 Cortactin is also a prognostic predictor for worse outcome for HCC tumors.16 "
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    ABSTRACT: Introduction Abl2 nonreceptor tyrosine kinase (Arg, c-abl oncogene 2) has recently been identified as being recurrently amplified at DNA levels and overexpressed at mRNA levels in hepatocellular carcinomas (HCCs), and might be a potential oncogenic driver and therapeutic target for HCC. Methods In this study, we investigated the Abl2 expression in a series of HCC tumors by immunohistochemistry and further evaluated its clinicopathological and prognostic significance. We also performed an in vitro experiment to validate the effect of Abl2 gene silencing on the migration and invasion abilities of human liver cancer HepG2 cells. Results It has been demonstrated that Abl2 was unregulated in 37.3% (28/75) of primary HCC tissues, and was significantly associated with a shorter overall survival time (P=0.0005). In addition, Abl2 gene silencing in HepG2 cells significantly attenuated its migration and invasion abilities in vitro. We also found that the phosphorylation of metastasis-associated gene cortactin was markedly decreased by Abl2 silencing. Conclusion We propose that Abl2 might be a potential candidate therapeutic target for HCCs and that targeted therapies against Abl2 in the treatment of HCCs deserve further investigation in the future.
    OncoTargets and Therapy 05/2014; 7:881-5. DOI:10.2147/OTT.S62348 · 2.31 Impact Factor
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