Chen W S, Lazar C S, Lund K A, Welsh J B, Chang C P, Walton G M, Der C J, Wiley H S, Gill G N, Rosenfeld M G
School of Medicine, University of California, San Diego, La Jolla 92093.
Cell. 1989 Oct 6;59(1):33-43. doi: 10.1016/0092-8674(89)90867-2.
We have located the distal boundary of the tyrosine kinase domain of the EGF receptor and have identified a distinct sequence in the C' terminus required for EGF-dependent receptor internalization, leading to receptor down-regulation and degradation. Within this receptor domain, an 18 amino acid highly negatively charged region of predicted helical structure is required both for endocytosis via a high-affinity, saturable pathway and for ligand-stimulated increases in cytosolic calcium. In contrast to kinase-inactive, internalization-competent receptors, kinase-active, internalization-defective receptors effectively signaled gene transcription, morphological transformation, and growth. These observations support the hypothesis that mitogenic responses to EGF are mediated by activation of the intrinsic protein tyrosine kinase activity of the membrane-bound receptor, with ligand-induced internalization serving to terminate the signal.
我们已确定表皮生长因子（EGF）受体酪氨酸激酶结构域的远端边界，并在C'末端鉴定出一个独特序列，该序列是EGF依赖的受体内化所必需的，可导致受体下调和降解。在该受体结构域内，一个由18个氨基酸组成的、预测具有螺旋结构的高度带负电荷区域，对于通过高亲和力、可饱和途径的内吞作用以及配体刺激引起的胞质钙增加都是必需的。与激酶无活性但具有内化能力的受体相反，激酶有活性但内化缺陷的受体有效地介导了基因转录、形态转化和生长信号。这些观察结果支持了这样一种假说，即对EGF的促有丝分裂反应是由膜结合受体的内在蛋白酪氨酸激酶活性的激活介导的，配体诱导的内化作用用于终止信号。
