BB, a novel epidermal growth factor receptor inhibitor.

摘要

A major class of the RTK superfamily is comprised of the HER or epidermal growth factor (EGF) receptors and consists of EGFR (ErbBl/HERl), HER2eu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). All family members contain an extracellular ligand-binding domain, a single membrane-spanning region, a juxtamembrane nuclear localization signal, and a cytoplasmic tyrosine kinase domain (TKD). Under homeostatic conditions, receptor activation is tightly regulated by the availability of ligands, which collectively form the EGF growth factor family. Ligand binding leads to receptor homo- or hetero-dimerization at the plasma membrane. This interaction activates the receptor tyrosine kinase and, thereby, causes autophosphorylation of the cytoplasmic tail. HER3 is the only family member that lacks intrinsic kinase activity, however, downstream signaling is achieved through heterodimerization. The EGFR contains several tyrosines and serines that are autophosphorylated and lead to several physiological functions (Fig. 1). The phosphorylated cytoplasmic tail serves as a docking site for numerous proteins that contain Src Homology (SH2) and phosphotyrosine binding domains (PB). EGFR activation stimulates many complex intracellular signaling pathways including the RAS/RAF/MEK7MAPK and the phosphatidylinositol 3-kinase (PI3K)-Akt axes. However, SRC tyrosine kinases, PLCy, PKC, and signal transducer and activator of transcription (STATs) activation have also been documented. Tumor cell proliferation, survival, invasion and angiogenesis ultimately can be promoted through the EGFR signaling pathway.