Aviezer D, Yayon A
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12173-7. doi: 10.1073/pnas.91.25.12173.
Heparin-binding EGF-like growth factor (HB-EGF) is a recently identified member of the EGF family of growth factors and a potent mitogen for smooth muscle cells and fibroblasts. Chinese hamster ovary (CHO) cells genetically engineered to express the human EGF receptor bind with high affinity both EGF and HB-EGF. CHO mutant cells lacking heparan sulfate proteoglycans (HSPG) bind EGF equally well to wild-type cells and EGF binding is not affected by exogenous heparin. However, HSPG-deficient EGF receptor-expressing cells do not bind significant levels of HB-EGF unless heparin is present in the binding medium. Moreover, binding of radiolabeled EGF to HSPG-deficient EGF receptor-expressing cells is efficiently displaced by nonlabeled HB-EGF only in the presence of heparin. Signal transduction by the EGF receptor tyrosine kinase as evidenced by receptor autophosphorylation is induced by HB-EGF only in the presence of heparin, in contrast to EGF-induced receptor autophosphorylation, which is independent of heparin. These results directly demonstrate that HB-EGF but not EGF requires heparin or cell surface HSPG for binding and activation of the EGF receptor and that HB-EGF receptor interactions can be tightly regulated by the available local concentration of heparin-like molecules.
肝素结合表皮生长因子样生长因子（HB-EGF）是最近发现的表皮生长因子家族成员，是平滑肌细胞和成纤维细胞的强效促有丝分裂原。经基因工程改造以表达人表皮生长因子受体的中国仓鼠卵巢（CHO）细胞与表皮生长因子和HB-EGF都具有高亲和力结合。缺乏硫酸乙酰肝素蛋白聚糖（HSPG）的CHO突变细胞与野生型细胞结合表皮生长因子的能力相同，且表皮生长因子的结合不受外源性肝素的影响。然而，缺乏HSPG的表达表皮生长因子受体的细胞不会结合显著水平的HB-EGF，除非结合介质中存在肝素。此外，仅在肝素存在的情况下，放射性标记的表皮生长因子与缺乏HSPG的表达表皮生长因子受体的细胞的结合才会被未标记的HB-EGF有效取代。与表皮生长因子诱导的受体自磷酸化（其独立于肝素）相反，仅在肝素存在的情况下，HB-EGF才能诱导由受体自磷酸化证明的表皮生长因子受体酪氨酸激酶的信号转导。这些结果直接表明，HB-EGF而非表皮生长因子需要肝素或细胞表面HSPG来结合和激活表皮生长因子受体，并且HB-EGF与受体的相互作用可以通过肝素样分子的可用局部浓度进行严格调节。
