EGFR, Faster than STATS?

Abstract

Although there have been a few reports that growth factor receptors cycle to the nucleus, there has not been much follow-up work attempting to answer why they are there. Lin et al. seem to have identified a role for epidermal growth factor receptors (EGFRs) in the nucleus: transcriptional activation. EGFR was found in the nucleus of cell lines and normal tissues that proliferate quickly, such as human buccal mucosa, as demonstrated by immunohistochemistry and isolation of cell nuclei. The majority of EGFR was phosphorylated in the nucleus and began to appear in the nucleus within 1 min of EGF treatment of cells. Nuclear fractions from EGFR-expressing cells treated with cross-linked 125 I-labeled EGF-EGFR contained the radiolabeled EGF-EGFR complexes, suggesting that the complexes relocalized from the plasma membrane to the nucleus. The authors identified a proline-rich region from the COOH-terminal portion of EGFR, purported to be similar to a transcriptional activation domain, and fused it to a Gal4 DNA binding domain. This construct greatly increased the expression of a Gal4-dependent reporter gene, whereas a construct that included the EGFR kinase domain in addition to the proline-rich domain and Gal4 DNA binding domain only slightly increased reporter gene expression. The authors concluded that this was evidence of a transactivation domain in EGFR and that the kinase domain acted to negatively regulate transactivation. However, taking specific regions away from the context of the full-length protein and evaluating them for specific activities is possibly to ascribe physiologically irrelevant functions to protein fragments. Nonetheless, Lin et al. identified an AT-rich sequence that bound to EGFR from EGF-treated cells in vitro and also found that EGFR bound to similar elements within the cyclin D1 promoter in chromatin immunoprecipitation assays. These results suggest that EGFR in the nucleus might increase cellular proliferation through the increased expression of cyclin D1. Additional work will need to be done to validate and further this work with other receptors; if these results remain robust and withstand scrutiny, then clearly, a brand new area of signaling research will have been opened. S.-Y. Lin, K. Makino, W. Xia, A. Matin, Y. Wen, K. Y. Kwong, L. Bourguignon, M.-C. Hung, Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nature Cell Biol. 3 , 802-808 (2001). [Online Journal]