TY - JOUR
T1 - Quantitation of the effect of ErbB2 on epidermal growth factor receptor binding and dimerization
AU - Li, Yu
AU - Macdonald-Obermann, Jennifer
AU - Westfall, Corey
AU - Piwnica-Worms, David
AU - Pike, Linda J.
PY - 2012/9/7
Y1 - 2012/9/7
N2 - The epidermal growth factor (EGF) receptor is a member of the ErbB family of receptors that also includes ErbB2, ErbB3, and ErbB4. These receptors form homo- and heterodimers in response to ligand with ErbB2 being the preferred dimerization partner. Here we use 125I-EGF binding to quantitate the interaction of the EGF receptor with ErbB2.Weshow that the EGFR/ErbB2 heterodimer binds EGF with a 7-fold higher affinity than the EGFR homodimer. Because it cannot bind a second ligand, the EGFR/ErbB2 heterodimer is not subject to ligand-induced dissociation caused by the negatively cooperative binding of EGF to the second site on the EGFR homodimer. This increases the stability of the heterodimer relative to the homodimer and is associated with enhanced and prolonged EGF receptor autophosphorylation. These effects are independent of the kinase activity of ErbB2 but require back-to-back dimerization of the EGF receptor with ErbB2. Back-to-back dimerization is also required for phosphorylation of ErbB2. These findings provide a molecular explanation for the apparent preference of the EGF receptor for dimerizing with ErbB2 and suggest that the phosphorylation of ErbB2 occurs largely in the context of the EGFR/ErbB2 heterodimer, rather than through lateral phosphorylation of isolated ErbB2 subunits.
AB - The epidermal growth factor (EGF) receptor is a member of the ErbB family of receptors that also includes ErbB2, ErbB3, and ErbB4. These receptors form homo- and heterodimers in response to ligand with ErbB2 being the preferred dimerization partner. Here we use 125I-EGF binding to quantitate the interaction of the EGF receptor with ErbB2.Weshow that the EGFR/ErbB2 heterodimer binds EGF with a 7-fold higher affinity than the EGFR homodimer. Because it cannot bind a second ligand, the EGFR/ErbB2 heterodimer is not subject to ligand-induced dissociation caused by the negatively cooperative binding of EGF to the second site on the EGFR homodimer. This increases the stability of the heterodimer relative to the homodimer and is associated with enhanced and prolonged EGF receptor autophosphorylation. These effects are independent of the kinase activity of ErbB2 but require back-to-back dimerization of the EGF receptor with ErbB2. Back-to-back dimerization is also required for phosphorylation of ErbB2. These findings provide a molecular explanation for the apparent preference of the EGF receptor for dimerizing with ErbB2 and suggest that the phosphorylation of ErbB2 occurs largely in the context of the EGFR/ErbB2 heterodimer, rather than through lateral phosphorylation of isolated ErbB2 subunits.
UR - http://www.scopus.com/inward/record.url?scp=84866081605&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.373647
DO - 10.1074/jbc.M112.373647
M3 - Article
C2 - 22822073
AN - SCOPUS:84866081605
SN - 0021-9258
VL - 287
SP - 31116
EP - 31125
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -