Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family

Receptor tyrosine kinases (RTKs), which contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain, mediate cellular signal transduction by extracellular ligand binding. The epidermal growth factor receptor (EGFR) family of RTKs consists of four members: EGFR/ErbB-1/HER-1, ErbB-2/HER-2/neu, ErbB-3/HER-3, and ErbB-4/HER-4, and all except ErbB-3 are associated with tyrosine kinase activity. Upon ligand binding, EGFR family proteins dimerize by receptor homo-dimerization or hetero-dimerization and subsequently activate tyrosine kinase activity. Activated EGFR family receptors then trigger a myriad of downstream signaling pathways, such as phosphatidylinositol-3 kinase, mitogen-activated protein kinase, signal transducer and activator of transcription (STAT), phospholipase C, and the modulation of calcium channels. These downstream signaling activities regulate proliferation, mobility, and differentiation in many different cell types [1-4].All but ErbB-4 of the EGFR family of proteins are expressed and/or constitutively activated in human tumors of epithelial origin. This expression leads to aggressive tumor behavior, including cancer initiation, increased tumor growth/progression, poor patient outcome, metastasis, and chemo-resistance [5-8]. Unlike the other EGFRs, the oncogenic role of ErbB-4 in breast cancer is unclear since it appears to be correlated with prolonged patient survival and tumor growth suppression [9,10]. Accordingly, EGFR family receptors have been considered as effective targets for anti-cancer therapies. Both ectodomain-binding monoclonal antibodies and small-molecule tyrosine-kinase inhibitors (TKIs) targeting EGFR and ErbB-2 have been developed, and many of them are approved by the Food and Drug Administration.Interestingly, in addition to their positions in traditional signaling cascades, numerous evidence to date from different groups indicate a unique translocation and the associated biol