Plowman G D, Culouscou J M, Whitney G S, Green J M, Carlton G W, Foy L, Neubauer M G, Shoyab M
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746-50. doi: 10.1073/pnas.90.5.1746.
This report describes the isolation and recombinant expression of a cDNA clone encoding HER4, the fourth member of the human epidermal growth factor receptor (EGFR) family. The HER4/erbB4 gene encodes a 180-kDa transmembrane tyrosine kinase (HER4/p180erbB4) whose extracellular domain is most similar to the orphan receptor HER3/p160erbB3, whereas its cytoplasmic kinase domain exhibits 79% and 77% identity with EGFR and HER2/p185erbB2, respectively. HER4 is most predominantly expressed in several breast carcinoma cell lines, and in normal skeletal muscle, heart, pituitary, brain, and cerebellum. In addition, we describe the partial purification of a heparin-binding HER4-stimulatory factor from HepG2 cells. This protein was found to specifically stimulate the intrinsic tyrosine kinase activity of HER4/p180erbB4 while having no direct effect on the phosphorylation of EGFR, HER2, or HER3. Furthermore, this heparin-binding protein induces phenotypic differentiation, and tyrosine phosphorylation, of a human mammary tumor cell line that overexpresses both HER4 and HER2. These findings suggest that this ligand-receptor interaction may play a role in the growth and differentiation of some normal and transformed cells.
本报告描述了编码HER4（人表皮生长因子受体（EGFR）家族的第四个成员）的cDNA克隆的分离和重组表达。HER4/erbB4基因编码一种180 kDa的跨膜酪氨酸激酶（HER4/p180erbB4），其胞外结构域与孤儿受体HER3/p160erbB3最为相似，而其胞质激酶结构域与EGFR和HER2/p185erbB2的同源性分别为79%和77%。HER4在几种乳腺癌细胞系以及正常骨骼肌、心脏、垂体、脑和小脑中表达最为显著。此外，我们描述了从HepG2细胞中部分纯化一种肝素结合型HER4刺激因子。发现该蛋白能特异性刺激HER4/p180erbB4的内在酪氨酸激酶活性，而对EGFR、HER2或HER3的磷酸化没有直接影响。此外，这种肝素结合蛋白可诱导同时过表达HER4和HER2的人乳腺肿瘤细胞系发生表型分化和酪氨酸磷酸化。这些发现表明，这种配体-受体相互作用可能在一些正常细胞和转化细胞的生长及分化中发挥作用。
