Plasma-membrane-anchored growth factor pro-amphiregulin binds A-type lamin and regulates global transcription
Plasma-membrane-anchored growth factor pro-amphiregulin binds A-type lamin and regulates global transcription
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DOI：
10.1242/jcs.031443
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发表时间：
2008-11-01
影响因子：
4
通讯作者：
Higashiyama, Shigeki
中科院分区：
文献类型：
--
作者：
Isokane, Mayumi;Hieda, Miki;Higashiyama, Shigeki
双调节蛋白（Amphiregulin， AR）是EGF家族的一员，作为I型跨膜蛋白前体（proAR）合成并在细胞表面表达。proAR的脱落产生一个跨膜细胞质片段（AR- ctf），以及一个可溶性的AR。在这里，我们证明了proAR脱落刺激会触发AR- ctf和未脱落的proAR的内吞作用。ProAR从质膜转运到内核膜，而AR-CTF则通过逆行膜转运转运到溶酶体。proAR的核膜定位涉及到c末端的截断，这随后激活er检索信号。截断形式的proAR与a型纤层蛋白相互作用并保留在核膜内。然后诱导异染色质形成，并暂时抑制全局转录。这项研究为哺乳动物细胞表观遗传染色质组织提供了新的见解：一种质膜锚定生长因子靶向于核膜内，参与动态染色质组织和转录控制。
Amphiregulin (AR), a member of the EGF family, is synthesized as a type I transmembrane protein precursor (proAR) and expressed on the cell surface. Shedding of proAR yields a transmembrane-cytoplasmic fragment (AR-CTF), as well as a soluble AR. Here we demonstrate that the proAR-shedding stimuli trigger endocytosis of both AR-CTF and un-shed proAR. ProAR translocates from the plasma membrane to the inner nuclear membrane, whereas AR-CTF is translocated to the lysosome via retrograde membrane trafficking. Nuclear envelope localization of proAR involves truncation of the C-terminus, which subsequently activates the ER-retrieval signal. The truncated form of proAR interacts with A-type lamin and is retained at the inner nuclear membrane. Heterochromatin formation is then induced and global transcription is transiently suppressed. This study gives new insight into epigenetic chromatin organization in mammalian cells: a plasma-membrane-anchored growth factor is targeted to the inner nuclear membrane where it participates in dynamic chromatin organization and control of transcription.