Processing of CD109 by furin and its role in the regulation of TGF-β signaling
Processing of CD109 by furin and its role in the regulation of TGF-β signaling
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DOI：
10.1038/onc.2009.506
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发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Takahashi, M.
中科院分区：
文献类型：
--
作者：
Hagiwara, S.;Murakumo, Y.;Takahashi, M.
CD109 是一种糖基磷脂酰肌醇 (GPI) 锚定糖蛋白，其表达在肺癌、食道癌、子宫癌和口腔鳞状细胞癌中上调。 CD109 通过直接调节受体活性来负调节角质形成细胞中的转化生长因子 (TGF)-β 信号传导。在这项研究中，我们进一步表征了 CD109 对 TGF-β 信号传导和细胞增殖的调节。我们发现CD109以205 kDa的糖蛋白形式产生，然后在高尔基体中被弗林蛋白酶（furinase）加工成180 kDa和25 kDa的蛋白质。 180 kDa CD109 与 GPI 锚定在细胞表面的 25 kDa CD109 相关，并且也分泌到培养基中。为了研究CD109的呋喃酶裂解对其生物活性是否是必需的，我们将CD109呋喃酶裂解基序中的精氨酸1273（氨基酸1270-RRRR-1273）突变为丝氨酸（R1273S）。有趣的是，CD109 R1273S 既不显着损害 TGF-β 信号传导，也不影响 TGF-β 介导的细胞生长抑制，尽管它在细胞表面表达为 205 kDa 蛋白。与这一发现一致的是，180 kDa 和 25 kDa CD109 复合物（而非 CD109 R1273S）与 I 型 TGF-β 受体相关。这些发现表明，弗林蛋白酶将 CD109 加工成 180 kDa 和 25kDa 蛋白，然后与 I 型 TGF-β 受体形成复合物，这是癌细胞和角质形成细胞中 TGF-β 信号传导的调节所必需的。癌基因 (2010) 29, 2181-2191; doi：10.1038/onc.2009.506； 2010 年 1 月 25 日在线发布
CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, whose expression is upregulated in squamous cell carcinomas of the lung, esophagus, uterus and oral cavity. CD109 negatively regulates transforming growth factor (TGF)-beta signaling in keratinocytes by directly modulating receptor activity. In this study, we further characterized CD109 regulation of TGF-beta signaling and cell proliferation. We found that CD109 is produced as a 205 kDa glycoprotein, which is then processed in the Golgi apparatus into 180 kDa and 25 kDa proteins by furin (furinase). 180 kDa CD109 associated with GPI-anchored 25 kDa CD109 on the cell surface and was also secreted into the culture medium. To investigate whether furinase cleavage of CD109 is necessary for its biological activity, we mutated arginine 1273 in the CD109 furinase cleavage motif (amino acid 1270-RRRR-1273) to serine (R1273S). Interestingly, CD109 R1273S neither significantly impaired TGF-beta signaling nor affected TGF-beta-mediated suppression of cell growth, although it was expressed on the cell surface as a 205 kDa protein. Consistent with this finding, the 180 kDa and 25 kDa CD109 complex, but not CD109 R1273S, associated with the type I TGF-beta receptor. These findings indicate that processing of CD109 into 180 kDa and 25kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes. Oncogene (2010) 29, 2181-2191; doi: 10.1038/onc.2009.506; published online 25 January 2010