Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Biol Chem. 2012 Sep 7;287(37):31116-25. doi: 10.1074/jbc.M112.373647. Epub 2012 Jul 20.
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 (125)I-EGF binding to quantitate the interaction of the EGF receptor with ErbB2. We show 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.
表皮生长因子（EGF）受体是 ErbB 受体家族的成员之一，该家族还包括 ErbB2、ErbB3 和 ErbB4。这些受体在配体的作用下形成同型和异型二聚体，其中 ErbB2 是首选的二聚化伴侣。在这里，我们使用 (125)I-EGF 结合来定量测定 EGF 受体与 ErbB2 的相互作用。我们表明，EGFR/ErbB2 异二聚体与 EGF 的结合亲和力比 EGFR 同二聚体高 7 倍。由于它不能结合第二个配体，因此 EGFR/ErbB2 异二聚体不受 EGF 对 EGFR 同二聚体第二结合位点的负协同结合引起的配体诱导解离的影响。这增加了异二聚体相对于同二聚体的稳定性，并与增强和延长 EGF 受体自身磷酸化相关。这些效应独立于 ErbB2 的激酶活性，但需要 EGF 受体与 ErbB2 背靠背二聚化。背靠背二聚化也是 ErbB2 磷酸化所必需的。这些发现为 EGF 受体与 ErbB2 二聚化的明显偏好提供了分子解释，并表明 ErbB2 的磷酸化主要发生在 EGFR/ErbB2 异二聚体的情况下，而不是通过孤立的 ErbB2 亚基的侧向磷酸化。
