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1.  Regulation of Invasive Behavior by Vascular Endothelial Growth Factor is HEF1-dependent 
Oncogene  2010;29(31):4449-4459.
We previously reported a VEGF autocrine loop in head and neck squamous cell carcinoma (HNSCC) cell lines, supporting a role for VEGF in HNSCC tumorigenesis. Using a phosphotyrosine proteomics approach we screened the HNSCC cell line, SCC-9 for effectors of VEGFR2 signaling. A cluster of proteins involved in cell migration and invasion, including the p130Cas paralog, human enhancer of filamentation1 (HEF1/Cas-L/Nedd9) was identified. HEF1 silencing and overexpression studies revealed a role for VEGF in regulating cell migration, invasion, and MMP expression in a HEF1-dependent manner. Moreover, cells plated on extracellular matrix coated coverslips exhibited enhanced invadopodia formation in response to VEGF that was HEF1-dependent. Immunolocalization revealed that HEF1 colocalized to invadopodia with MT1-MMP. Analysis of HNSCC tissue microarrays for HEF1 immunoreactivity revealed a 6.5-fold increase in the odds of having a metastasis with a high HEF1 score compared to a low HEF1 score. These findings suggest that HEF1 may be prognostic for advanced stage HNSCC. They also demonstrate for the first time, that HEF1 is required for VEGF-mediated HNSCC cell migration and invasion, consistent with HEF1’s recent identification as a metastatic regulator. These results support a strategy targeting VEGF:VEGFR2 in HNSCC therapeutics.
PMCID: PMC2921319  PMID: 20498643
VEGF; Invadopodia; Cell migration; invasion; HEF1; NEDD9; CAS-L; tyrosine phosphorylation

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