Liu Jie, Rothermund Christy A, Ayala-Sanmartin Jesus, Vishwanatha Jamboor K
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
BMC Biochem. 2003 Sep 9;4:10. doi: 10.1186/1471-2091-4-10.
Annexin II heavy chain (also called p36, calpactin I) is lost in prostate cancers and in a majority of prostate intraepithelial neoplasia (PIN). Loss of annexin II heavy chain appears to be specific for prostate cancer since overexpression of annexin II is observed in a majority of human cancers, including pancreatic cancer, breast cancer and brain tumors. Annexin II exists as a heterotetramer in complex with a protein ligand p11 (S100A10), and as a monomer. Diverse cellular functions are proposed for the two forms of annexin II. The monomer is involved in DNA synthesis. A leucine-rich nuclear export signal (NES) in the N-terminus of annexin II regulates its nuclear export by the CRM1-mediated nuclear export pathway. Mutation of the NES sequence results in nuclear retention of annexin II.
Annexin II localized in the nucleus is phosphorylated, and the appearance of nuclear phosphorylated annexin II is cell cycle dependent, indicating that phosphorylation may play a role in nuclear entry, retention or export of annexin II. By exogenous expression of annexin II in the annexin II-null LNCaP cells, we show that wild-type annexin II is excluded from the nucleus, whereas the NES mutant annexin II localizes in both the nucleus and cytoplasm. Nuclear retention of annexin II results in reduced cell proliferation and increased doubling time of cells. Expression of annexin II, both wild type and NES mutant, causes morphological changes of the cells. By site-specific substitution of glutamic acid in the place of serines 11 and 25 in the N-terminus, we show that simultaneous phosphorylation of both serines 11 and 25, but not either one alone, prevents nuclear localization of annexin II.
Our data show that nuclear annexin II is phosphorylated in a cell cycle-dependent manner and that substitution of serines 11 and 25 inhibit nuclear entry of annexin II. Aberrant accumulation of nuclear annexin II retards proliferation of LNCaP cells.
膜联蛋白II重链（也称为p36、钙结合蛋白I）在前列腺癌和大多数前列腺上皮内瘤变（PIN）中缺失。膜联蛋白II重链的缺失似乎是前列腺癌所特有的，因为在大多数人类癌症中，包括胰腺癌、乳腺癌和脑肿瘤，都观察到膜联蛋白II的过表达。膜联蛋白II以与蛋白质配体p11（S100A10）形成的异源四聚体形式以及单体形式存在。两种形式的膜联蛋白II具有多种细胞功能。单体参与DNA合成。膜联蛋白II N端富含亮氨酸的核输出信号（NES）通过CRM1介导的核输出途径调节其核输出。NES序列的突变导致膜联蛋白II在细胞核内滞留。
定位于细胞核的膜联蛋白II被磷酸化，并且核磷酸化膜联蛋白II的出现是细胞周期依赖性的，这表明磷酸化可能在膜联蛋白II的核进入、滞留或输出中起作用。通过在膜联蛋白II缺失的LNCaP细胞中外源表达膜联蛋白II，我们发现野生型膜联蛋白II被排除在细胞核外，而NES突变型膜联蛋白II定位于细胞核和细胞质中。膜联蛋白II在细胞核内滞留导致细胞增殖减少和细胞倍增时间增加。野生型和NES突变型膜联蛋白II的表达都会引起细胞形态变化。通过将N端的丝氨酸11和25位点特异性替换为谷氨酸，我们发现丝氨酸11和25同时磷酸化，但单独一个丝氨酸磷酸化则不能阻止膜联蛋白II的核定位。
我们的数据表明，核膜联蛋白II以细胞周期依赖性方式被磷酸化，并且丝氨酸11和25的替换抑制膜联蛋白II的核进入。核膜联蛋白II的异常积累会阻碍LNCaP细胞的增殖。
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