SMURF1 Plays a role in EGF-induced breast cancer cell migration and invasion
Epidermal growth factor (EGF) is a well-known growth factor that induces cancer cell migration and invasion. Previous studies have shown that SMAD ubiquitination regulatory factor 1 (SMURF1), an E3 ubiquitin ligase, regulates cell motility by inducing RhoA degradation. Therefore, we examined the role of SMURF1 in EGF-induced cell migration and invasion using MDA-MB-231 cells, a human breast cancer cell line. EGF increased SMURF1 expression at both the mRNA and protein levels. All ErbB family members were expressed in MDA-MB-231 cells and receptor tyrosine kinase inhibitors specific for the EGF receptor (EGFR) or ErbB2 blocked the EGF-mediated induction of SMURF1 expression. Within the signaling pathways examined, ERK1/2 and protein kinase C activity were required for EGF-induced SMURF1 expression. The overexpression of constitutively active MEK1 increased the SMURF1 to levels similar to those induced by EGF. SMURF1 induction by EGF treatment or by the overexpression of MEK1 or SMURF1 resulted in enhanced cell migration and invasion, whereas SMURF1 knockdown suppressed EGF- or MEK1-induced cell migration and invasion. EGF treatment or SMURF1 overexpression decreased the endogenous RhoA protein levels. The overexpression of constitutively active RhoA prevented EGF- or SMURF1-induced cell migration and invasion. These results suggest that EGFinduced SMURF1 plays a role in breast cancer cell migration and invasion through the downregulation of RhoA.
Keywordsbreast cancer EGF invasion migration SMURF1
Unable to display preview. Download preview PDF.
- Barr, S., Thomson, S., Buck, E., Russo, S., Petti, F., Sujka-Kwok, I., Eyzaguirre, A., Rosenfeld-Franklin, M., Gibson, N.W., Miglarese, M., et al. (2008). Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clin. Exp. Metastasis. 25, 685–693.PubMedCentralPubMedCrossRefGoogle Scholar
- Brandt, B.H., Roetger, A., Dittmar, T., Nikolai, G., Seeling, M., Merschjann, A., Nofer, J.R., Dehmer-Moller, G., Junker, R., Assmann, G., et al. (1999). c-erbB-2/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells. FASEB J. 13, 1939–1949.PubMedGoogle Scholar
- Cardoso, A.P., Pinto, M.L., Pinto, A.T., Oliveira, M.I., Pinto, M.T., Goncalves, R., Relvas, J.B., Figueiredo, C., Seruca, R., Mantovani, A., et al. (2013). Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y, c-Src, Erk1/2 and Akt phosphorylation and small GTPase activity. Oncogene [Epub ahead of print] doi: 10.1038/onc.2013.154Google Scholar
- Dittmar, T., Husemann, A., Schewe, Y., Nofer, J.R., Niggemann, B., Zanker, K.S., and Brandt, B.H. (2002). Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. FASEB J. 16, 1823–1825.PubMedGoogle Scholar
- Gril, B., Palmieri, D., Bronder, J.L., Herring, J.M., Vega-Valle, E., Feigenbaum, L., Liewehr, D.J., Steinberg, S.M., Merino, M.J., Rubin, S.D., et al. (2008). Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J. Natl. Cancer Inst. 100, 1092–1103.PubMedCrossRefGoogle Scholar
- Lee, H.L., Yi, T., Baek, K., Kwon, A., Hwang, H.R., Qadir, A.S., Park, H.J., Woo, K.M., Ryoo, H.M., Kim, G.S., et al. (2013). Tumor necrosis factor-alpha enhances the transcription of Smad ubiquitination regulatory factor 1 in an activating protein-1- and Runx2-dependent manner. J. Cell. Physiol. 228, 1076–1086.PubMedCrossRefGoogle Scholar
- Suzuki, A., Shibata, T., Shimada, Y., Murakami, Y., Horii, A., Shiratori, K., Hirohashi, S., Inazawa, J., and Imoto, I. (2008). Identification of SMURF1 as a possible target for 7q21.3–22.1 amplification detected in a pancreatic cancer cell line by in-house array-based comparative genomic hybridization. Cancer Sci. 99, 986–994.PubMedCrossRefGoogle Scholar