The nuclear epidermal growth factor receptor signaling network and its role in cancer

Abstract

The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (RTKs). EGFR activation via ligand binding results in signaling through various pathways ultimately resulting in cellular proliferation, survival, angiogenesis, invasion, and metastasis. Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, pancreatic cancer, and brain cancer. Thus intense efforts have been made to inhibit the activity of EGFR by designing antibodies against the ligand binding domains (cetuximab and panitumumab) or small molecules against the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib). Although targeting membrane-bound EGFR has shown benefit, a new and emerging role for EGFR is now being elucidated. In this review we will summarize the current knowledge of the nuclear EGFR signaling network, including how it is trafficked to the nucleus, the functions it serves in the nucleus, and how these functions impact cancer progression, survival, and response to chemotherapeutics.

Figure 1. Classical EGFR Signaling

Ligand binding to the EGFR activates the intrinsic tyrosine kinase activity of the EGFR and leads to the phosphorylation of specific tyrosines on the cytoplasmic tails of the receptor pair. These phospho-tyrosines serve to recruit specific effector molecules to activate several signaling pathways including the PI3K/AKT (A), RAS/MAPK (B), PLCγ/PKC (C) and STATs (D) pathways.

Figure 2. EGFR Trafficking from the cell surface to the nucleus

EGF stimulation at the cell surface induces receptor dimerization and internalization to endocytic vesicles (EV). EGFR then undergoes COPI-mediated retrograde translocation through the Golgi apparatus to the endoplasmic reticulum (ER)(Wang et al., 2010a). At the ER, EGFR moves from the outer nuclear membrane (ONM) to the inner nuclear membrane (INM) via interaction between importin β (β) and the nuclear pore complex (NPC). In the INM EGFR interacts with Sec61 for removal from the membrane and release into the nucleus(Wang et al., 2010b).

Figure 3. Nuclear EGFR Signaling Network

EGFR has been consistently detected in the nuclei of cancer cells, primary tumor specimens and highly proliferative tissues. EGFR binds to several transcription factors to regulate gene transcription of cyclin D1(Lin et al., 2001), iNOS(Lo et al., 2005a), B-Myb(Hanada et al., 2006), Aurora Kinase A(Hung et al., 2008), COX2(Lo et al., 2010), Myc(Jaganathan et al., 2011) and BCRP(Huang et al., 2011). In addition, EGFR has been shown to phosphorylate and activate both PCNA(Wang et al., 2006) and DNA-PK(Dittmann et al., 2005a) within the nucleus.