Quian X L, Decker S J, Greene M I
Department of Biology, University of Pennsylvania, School of Medicine, Philadelphia 19104-6082.
Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1330-4. doi: 10.1073/pnas.89.4.1330.
The protein product of the neu protooncogene, p185c-neu, is structurally similar to the epidermal growth factor receptor (EGFR). Overexpression of these two receptor tyrosine kinases, but not either separately, leads to transformation and tumorigenicity. Heterodimerization of p185c-neu and EGFR occurs in M1 cells, which express both receptors. We have individually identified the two components of the heterodimer as EGFR and p185c-neu. Analysis of this association with relatively nondenaturing detergents and in the absence of cross-linkers indicates that noncovalent interactions are primarily responsible for heterodimer formation. The rapid reversible heterodimerization was promoted by EGF binding to its receptor. Functionally, the heterodimer is a highly active protein kinase for receptor autophosphorylation and exogenous substrate phosphorylation in vitro. The isolated heterodimer was highly phosphorylated on tyrosine residues in vivo. These results indicate that the physical association between EGFR and p185c-neu is of functional significance and define enzymatic features of complex receptor formation.
神经原癌基因的蛋白质产物p185c-neu在结构上与表皮生长因子受体（EGFR）相似。这两种受体酪氨酸激酶的过表达（而非单独一种的过表达）会导致细胞转化和致瘤性。p185c-neu和EGFR的异源二聚化发生在同时表达这两种受体的M1细胞中。我们已分别鉴定出异源二聚体的两个组分是EGFR和p185c-neu。在相对非变性去污剂存在且无交联剂的情况下对这种结合进行分析表明，非共价相互作用是异源二聚体形成的主要原因。表皮生长因子与其受体的结合促进了快速可逆的异源二聚化。在功能上，异源二聚体是一种在体外对受体自身磷酸化和外源底物磷酸化具有高活性的蛋白激酶。分离出的异源二聚体在体内酪氨酸残基上高度磷酸化。这些结果表明EGFR和p185c-neu之间的物理结合具有功能意义，并确定了复合受体形成的酶学特征。
