Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors

Abstract

Integral membrane proteins contain a hydrophobic transmembrane domain and mainly locate in the plasma membrane lipid bilayer. The receptor tyrosine kinases (RTK) of the epidermal growth factor receptor (EGFR) superfamily, including ErbB-1, ErbB-2, ErbB-3, and ErbB-4, constitute an important group of such membrane proteins, which have a profound impact on cancer initiation, progression, and patient outcome. Although studies of their functions have conventionally focused on their membrane-associated forms, documented observations of the presence of these membrane receptors and their functioning partners in the nucleus have reshaped the intracellular geography and highlight the need to modify the central dogma. The ErbB proteins in the membrane can translocate to the nucleus through different mechanisms. Nuclear RTKs regulate a variety of cellular functions, such as cell proliferation, DNA damage repair, and signal transduction, both in normal tissues and in human cancer cell. In addition, they play important roles in determining cancer response to cancer therapy. Nuclear presence of these ErbB proteins is emerging as an important marker in human cancers. An integrated picture of the RTK-centered signaling transduction network extending from the membrane-cytoplasm boundary to the nuclear compartment is looming in the foreseeable horizon for clinical application.

Fig. 1

A working model of RTK functions in the nucleus. EGFR and ErbB-2 can function in transcriptional regulation. EGFR transactivates cyclin D1, iNOS, and Aurora-A together with the transcriptional factor STAT3 and STAT5. EGFR and E2F1 can stimulate transcription of the B-MYB gene. The AT-rich sequence (ATRS) on the promoter is important for the EGFR-mediated transactivation. Nuclear ErbB-2 transactivate the COX-2 gene through a HER2-associated sequence (HAS). The transcriptional factors involved remain to be identified. Nuclear EGFR can also function as a kinase to phosphorylate PCNA and increases its stability on the chromatin. Nuclear EGFR interacts with DNA-PK and convey a resistance phenotype to ionizing irradiation. It remains to be determined whether EGFR phosphorylates DNA-PK. ErbB-2 has been shown to phosphorylate the cyclin-dependent kinase p34CDC2, which causes G2-M arrest in cancer cells and subsequently leads to resistance to taxol treatment.