Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research

摘要: The EGF receptor (EGFR) and HER2 are members of a growth factor family. Overexpression either protein in advanced breast cancer correlates with poor prognosis. stimulates by binding to EGFR, activating the receptor's intracellular tyrosine kinase. initial consequence is phosphorylation specific tyrosine-containing sequences carboxyl terminus. These phosphotyrosines serves as high affinity recognition sites for proteins that, turn, transmit signal inside cell. Mechanistic studies suggest that binds single triggering dimerization another like molecule. This thought initiate kinase activation. family was recently expanded sequencing HER3 HER4. Each four postulated regulate unique or differentiation signaling repertoire when activated receptor-specific ligand. However, new data from numerous laboratories EGFR may play complex ultimately more flexible role forming heterodimers between members, e.g. EGFR:HER2 HER4:HER2. form even only one member pair its review summarizes current work on heterodimerization attempts predict consequences downstream signaling. In brief, compared ligand-dependent homodimers comprised two same internalization sequence phosphorylated residues, likely to: i) expand substrate selection pathway activation; ii) promote interaction sets substrates mixed complexes would not ordinarily be physically juxtaposed; iii) alter duration changing rates internalization, ligand loss, inactivation, recycling, etc.; iv) dephosphorylation. addition understanding interactions machinery, identification each will necessary explicate differentiation.