Hic-5 communicates between focal adhesions and the nucleus through oxidant-sensitive nuclear export signal
Hic-5 communicates between focal adhesions and the nucleus through oxidant-sensitive nuclear export signal
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DOI：
10.1091/mbc.02-06-0099
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发表时间：
2003-03-01
影响因子：
3.3
通讯作者：
Nose, K
中科院分区：
文献类型：
--
作者：
Shibanuma, M;Kim-Kaneyama, J;Nose, K
hic-5最初是作为H2 O2诱导的cDNA克隆分离的，其产物通常在粘着斑处发现。在这项研究中，我们发现Hic-5在细胞核中积累，以响应氧化剂，如H2 O2。其他粘着斑蛋白，包括桩蛋白，最同源的Hic-5，留在细胞质中。突变分析表明，C-和N-末端的一半的Hic-5有助于其核定位在一个积极和消极的方式，分别。在发现核输出信号（内斯）抑制剂来普霉素B（LMB）导致Hic-5滞留在细胞核中之后，证明Hic-5在对氧化剂敏感的N-末端具有内斯，从而调节Hic-5的核积累。内斯由一个富含亮氨酸的片段和两个半胱氨酸组成，与雅普/Pap-type内斯具有有限的相似性。在细胞核中，Hic-5可能参与c-fos基因的表达。利用显性失活突变体，我们发现Hic-5实际上是参与内源性c-fos基因表达后H2 O2处理。因此，Hic-5被认为是一种粘着斑蛋白，其新颖的方面是通过氧化剂敏感的内斯在粘着斑和细胞核之间穿梭，介导氧化还原信号直接到达细胞核。
hic-5 was originally isolated as an H2O2-inducible cDNA clone whose product was normally found at focal adhesions. In this study, we found that Hic-5 accumulated in the nucleus in response to oxidants such as H2O2. Other focal adhesion proteins including paxillin, the most homologous to Hic-5, remained in the cytoplasm. Mutation analyses revealed that the C- and N-terminal halves of Hic-5 contributed to its nuclear localization in a positive and negative manner, respectively. After the finding that leptomycin B (LMB), an inhibitor of nuclear export signal (NES), caused Hic-5 to be retained in the nucleus, Hic-5 was demonstrated to harbor NES in the N-terminal, which was sensitive to oxidants, thereby regulating the nuclear accumulation of Hic-5. NES consisted of a leucine-rich stretch and two cysteines with a limited similarity to Yap/Pap-type NES. In the nucleus, Hic-5 was suggested to participate in the gene expression of c-fos. Using dominant negative mutants, we found that Hic-5 was actually involved in endogenous c-fos gene expression upon H2O2 treatment. Hic-5 was thus proposed as a focal adhesion protein with the novel aspect of shuttling between focal adhesions and the nucleus through an oxidant-sensitive NES, mediating the redox signaling directly to the nucleus.