Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway

Abstract

Epidermal growth factor receptor (EGFR) exists in the nucleus of highly proliferative cells where it functions as a transcription factor. Although EGFR has transactivational activity, it lacks a DNA binding domain and, therefore, may require a DNA binding transcription cofactor for its transcriptional function. Here, we report that EGFR physically interacts with signal transducers and activators of transcription 3 (STAT3) in the nucleus, leading to transcriptional activation of inducible nitric oxide synthase (iNOS). In breast carcinomas, nuclear EGFR positively correlates with iNOS. This study describes a mode of transcriptional control involving cooperated efforts of STAT3 and nuclear EGFR. Our work suggests that the deregulated iNOS/NO pathway may partly contribute to the malignant biology of tumor cells with high levels of nuclear EGFR and STAT3.

Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival

“…In addition, EGFR has been shown to localize in the inner nuclear membrane (Cao et al, 1995;Klein et al, 2004). Nuclear counterpart of EGFR appears to be the full-length receptor and likely, in the phosphorylated form, as shown by a number of studies (Cao et al, 1995;Lin et al, 2001;Cordero et al, 2002;Dittmann et al, 2005a;Lo et al, 2005a, c). Consistently, EGF and pro-TGF-a were found to translocate into the nucleus of proliferating hepatocytes (Raper et al, 1987;Schausberger et al, 2003).…”

“…Nuclear expression of EGFR was further detected in other cell types and tissues, such as placentas, thyroids and immortalized epithelial cells of ovary and kidney origins (Cao et al, 1995;Lin et al, 2001;Marti et al, 2001;Lo et al, 2005a). High levels of EGFR was also found in the nuclei of many tumours, including those of skin, breast, bladder, cervix, adrenocorticord, thyroid and oral cavity (Kamio et al, 1990;Lipponen and Eskelinen, 1994;Lin et al, 2001;Marti et al, 2001;Lo et al, 2005a, c;Psyrri et al, 2005). In addition, EGFR has been shown to localize in the inner nuclear membrane (Cao et al, 1995;Klein et al, 2004).…”

“…Consistently, nuclear accumulation of EGFR correlates with increased expression of cyclin D1, inducible nitric oxide synthase (iNOS) and B-Myb, all of which are frequently overexpressed in human cancers and associated with increased cell proliferation (Lin et al, 2001;Hanada et al, 2005;Lo et al, 2005a). Furthermore, most recent reports indicate a plausible mechanism underlying nuclear EGFR-mediated gene regulation, which involves a physical interaction with other transcription factors, signal transducer and activator of transcription 3 (STAT3) and E2F1 (Hanada et al, 2005;Lo et al, 2005a). A cellular mechanism that can potentially account for nuclear import of receptor tyrosine kinases (RTKs) is also proposed recently (Giri et al, 2005).…”

“…Increased expression of nuclear EGFR is linked to poor clinical outcome in patients with breast carcinomas (Lo et al, 2005c) and oropharyngeal squamous cell carcinomas (Psyrri et al, 2005). Consistently, nuclear accumulation of EGFR correlates with increased expression of cyclin D1, inducible nitric oxide synthase (iNOS) and B-Myb, all of which are frequently overexpressed in human cancers and associated with increased cell proliferation (Lin et al, 2001;Hanada et al, 2005;Lo et al, 2005a). Furthermore, most recent reports indicate a plausible mechanism underlying nuclear EGFR-mediated gene regulation, which involves a physical interaction with other transcription factors, signal transducer and activator of transcription 3 (STAT3) and E2F1 (Hanada et al, 2005;Lo et al, 2005a).…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…EGFR has been proposed as a transcription factor as localization to the nucleus is associated with increased CyclinD1 expression [64]. Nuclear EGFR has also been shown to participate with STAT3 and E2F1 transcription factors in iNOS/NO pathway activation and B-myb expression, respectively [71,72]. Targeting to the nucleus seems to require three clusters of basic amino acids in the juxtamembrane domain of all ErbB family members that share homology with known nuclear localization sequences [73].…”