Fig. 1.

Cytoplasmic/traditional and nuclear modes of the epidermal growth factor receptor (EGFR) signalling pathway. The EGFR signalling pathway exerts its biological effects via two major modes of actions, namely, cytoplasmic/traditional (A) and nuclear (B) modes. (A) The cytoplasmic EGFR pathway is consisted of four major modules: PLC-γ-CaMK/PKC, Ras-Raf-MAPK, PI-3K-Akt-GSK and signal transducer and activator of transcriptions (STATs). Activation of these signalling modules often leads to tumorigenesis, tumour proliferation, metastasis, chemoresistance and radioresistance. (B) The nuclear EGFR pathway can be initiated by ligand binding and exposure to vitamin D, radiation, cisplatin, heat and H₂O₂. Following nuclear translocalization, nuclear EGFR interacts with DNA-binding transcription factors, E2F1 and STAT3, and activates expression of B-Myb and inducible nitric oxide synthase (iNOS), respectively. Nuclear EGFR also upregulates cyclin D1 gene expression. Increased expression of cyclin D1 and B-Myb contributes to accelerated G1/S cell cycle progression and, on the other hand, elevated iNOS is associated with tumour proliferation and metastasis. Upon DNA damage and oxidative/heat stress, EGFR enters the cell nucleus and interacts with DNA-PK, leading to DNA repair and radioresistance. Reprinted from Lo and Hung [23].