Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane
Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane
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DOI：
10.1083/jcb.200710022
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发表时间：
2008-02-25
影响因子：
7.8
通讯作者：
Higashiyama, Shigeki
中科院分区：
文献类型：
--
作者：
Hieda, Miki;Isokane, Mayumi;Higashiyama, Shigeki
肝素结合的表皮生长因子样生长因子(HB-EGF)是一种I型跨膜蛋白(proHB-EGF)，可在细胞表面表达。ProHB-EGF在细胞膜上的胞外区脱落，产生一个可溶性的EGF受体配体和一个跨膜-细胞质片段(HB-EGF-CTF)。HB-EGF的胞浆结构域(HB-EGF-cyto)与转录抑制因子相互作用，逆转其抑制活性。然而，HB-EGF-Cyto如何访问转录抑制物尚不清楚。本研究表明，在受到脱落刺激后，HB-EGF-CTF和未脱落的ProHB-EGF均移位到核膜。免疫电子显微镜和洋地黄素通透性细胞显示HB-EGF-Cyto信号位于核膜内侧。HB-EGF-Cyto中的短序列元件允许跨膜蛋白定位于核膜。显性活性形式的Rab5和Rab11抑制核包膜靶向。总之，这些数据表明，膜锚定的HB-EGF通过逆行膜转运途径靶向于内核膜。
Heparin-binding EGF-like growth factor (HB-EGF) is synthesized as a type I transmembrane protein (proHB-EGF) and expressed on the cell surface. The ectodomain shedding of proHB-EGF at the extracellular region on the plasma membrane yields a soluble EGF receptor ligand and a transmembrane-cytoplasmic fragment (HB-EGF-CTF). The cytoplasmic domain of proHB-EGF (HB-EGF-cyto) interacts with transcriptional repressors to reverse their repressive activities. However, how HB-EGF-cyto accesses transcriptional repressors is yet unknown. The present study demonstrates that, after exposure to shedding stimuli, both HB-EGF-CTF and unshed proHB-EGF translocate to the nuclear envelope. Immunoelectron microscopy and digitonin-permeabilized cells showed that HB-EGF-cyto signals are at the inner nuclear membrane. A short sequence element within the HB-EGF-cyto allows a transmembrane protein to localize to the nuclear envelope. The dominant-active form of Rab5 and Rab11 suppressed nuclear envelope targeting. Collectively, these data demonstrate that membrane-anchored HB-EGF is targeted to the inner nuclear membrane via a retrograde membrane trafficking pathway.