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. Author manuscript; available in PMC: 2016 Aug 1.
Published in final edited form as: Gene. 2015 May 9;567(1):1–11. doi: 10.1016/j.gene.2015.04.086

Figure 3. NEDD9 signaling mechanisms analyzed in breast cancer models.

Figure 3

NEDD9 is activated by FAK and SRC kinases, and also helps support continuous activation of these kinases [56]. NEDD9 mediates TGFβ effects through a positive feedback loop [61]. Transcription factors SRF (serum response factor) and SMAD induce NEDD9 expression; NEDD9 scaffolding connects TGFβ/SMAD and Rho-actin-SRF signals to coordinate the expression of genes involved in tumorigenesis [61]. NEDD9 binding to the DOCK3 GEF activates RAC, which signals through WAVE/SCAR to initiate ARP2/3-dependent actin branching, lamellipodia formation, and MMP activation [69]. NEDD9 and SRC negatively regulate expression of E-cadherin through upregulation of the SLUG and SNAIL transcription factors [60], and also by regulating SRC-dependent removal of E-cadherin from adherens junctions [68]. NEDD9 promotes trafficking of ligand-bound integrins from early to late endosomes and degradation of ligand/integrin complexes by inactivating caveolin (CAV1), which mediates recycling of ligand-bound integrins from early endosomes back to the plasma membrane [65]. NEDD9 regulates turnover of MMP14 and its enzymatic recovery through the late endosomes by suppressing Arf6 dependent trafficking of MMP14/TIMP2 complexes from early/sorting endosomes back to the surface. MMP14 cleaves pro-MMP2 to produce active MMP2, degrading type IV collagen of basal membrane and promoting invasion [66]. FAK – focal adhesion kinase; SRC – (short for sarcoma), proto-oncogene non-receptor tyrosine kinase Src; SRF - Serum response factor; SMAD – homolog of C. Elegans protein SMA (from gene sma for small body size) and Drosophila protein MAD (mothers against decapentaplegic); DOCK3 – Dedicator of cytokinesis 3; SLUG, SNAIL – members of SNAIL family zinc finger transcription factors; ARP2/3 – protein complex regulating actin cytoskeleton; WAVE member of the Wiskott-Aldrich syndrome family protein, activates ARP2/3 complex; MMP - matrix metalloproteinase TIMP2 – metallopeptidase inhibitor 2; ARF6 – ADP-ribosylation factor 6; CAV1 – caveolin 1.