Herstatin, an autoinhibitor of the human epidermal growth factor receptor 2 tyrosine kinase, modulates epidermal growth factor signaling pathways resulting in growth arrest
Herstatin, an autoinhibitor of the human epidermal growth factor receptor 2 tyrosine kinase, modulates epidermal growth factor signaling pathways resulting in growth arrest
复制标题
DOI：
10.1074/jbc.m111359200
复制
发表时间：
2002-06-07
影响因子：
4.8
通讯作者：
Clinton, GM
中科院分区：
文献类型：
--
作者：
Justman, QA;Clinton, GM
Herstatin 是 ErbB 家族的一种自身抑制剂，由人表皮生长因子受体 2 (ErbB-2) 胞外结构域的子结构域 I 和 II 以及由内含子编码的新型 C 末端结构域组成。 Herstatin 与人表皮生长因子受体 2 和表皮生长因子受体 (EGFR) 结合，阻断受体寡聚化和酪氨酸磷酸化。在这项研究中，我们描述了 EGFR 激活的几个早期步骤，并研究了在表达 EGFR 的 NIH3T3 细胞系中，在有或没有赫他汀的情况下，表皮生长因子 (EGF) 和转化生长因子 a (TGF-α) 诱导的下游信号转导事件。尽管受体被具有正常结合亲和力的配体占据，但 Herstatin 表达降低了 EGF 诱导的 EGFR 酪氨酸磷酸化并延迟了受体下调。在 Herstatin 存在的情况下，EGF 和 TGF-α（而非成纤维细胞生长因子 2）对 Akt 的刺激几乎被完全阻断。令人惊讶的是，EGF 和 TGF-α 在持续时间和强度上诱导 MAPK 完全激活，并刺激 EGFR 与 She 和 Grb2 的关联。尽管 MAPK 被充分刺激，但 Herstatin 的表达阻止了 TGF-α 诱导的 DNA 合成和 EGF 诱导的增殖。在共转染 EGFR 和 Herstatin 的中国仓鼠卵巢细胞中也观察到 Herstatin 介导的 MAPK 与 Akt 激活的解偶联。这些发现表明 Herstatin 表达改变 EGF 和 TGF-α 信号传导谱，最终抑制增殖。
Herstatin is an autoinhibitor of the ErbB family consisting of subdomains I and II of the human epidermal growth factor receptor 2 (ErbB-2) extracellular domain and a novel C-terminal domain encoded by an intron. Herstatin binds to human epidermal growth factor receptor 2 and to the epidermal growth factor receptor (EGFR), blocking receptor oligomerization and tyrosine phosphorylation. In this study, we characterized several early steps in EGFR activation and investigated downstream signaling events induced by epidermal growth factor (EGF) and by transforming growth factor a (TGF-alpha) in NIH3T3 cell lines expressing EGFR with and without herstatin. Herstatin expression decreased EGF-induced EGFR tyrosine phosphorylation and delayed receptor down-regulation despite receptor occupancy by ligand with normal binding affinity. Akt stimulation by EGF and TGF-alpha, but not by fibroblast growth factor 2, was almost completely blocked in the presence of herstatin. Surprisingly, EGF and TGF-alpha induced full activation of MAPK in duration and intensity and stimulated association of the EGFR with She and Grb2. Although MAPK was fully stimulated, herstatin expression prevented TGF-alpha-induced DNA synthesis and EGF-induced proliferation. The herstatin-mediated uncoupling of MAPK from Akt activation was also observed in Chinese hamster ovary cells co-transfected with EGFR and herstatin. These findings show that herstatin expression alters EGF and TGF-alpha signaling profiles, culminating in inhibition of proliferation.