Protein phosphatase type 2A, PP2A, is involved in degradation of gp130
Protein phosphatase type 2A, PP2A, is involved in degradation of gp130
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DOI：
10.1007/s11010-005-3089-x
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发表时间：
2005-01-01
影响因子：
4.3
通讯作者：
Kikuchi, K
中科院分区：
文献类型：
--
作者：
Mitsuhashi, S;Shima, H;Kikuchi, K
白细胞介素 6 (IL-6) 刺激多发性骨髓瘤和 B 细胞浆细胞瘤/杂交瘤等细胞的生长，同时抑制多种骨髓性白血病细胞的生长。 IL-6 受体有一个名为 gp130 的亚基。据报道，gp130 的 Ser-782 被细胞提取物中的不明激酶磷酸化，COS-7 细胞表面瞬时表达的 gp130 (S782A) 水平比野生型高 6 倍。这些结果促使我们分析 gp130 Ser-782 的磷酸化是否参与其降解。在这项研究中，我们证明用 PP2A 强效抑制剂冈田酸 (OA) 处理 HepG2 细胞可促进 gp130 Ser-782 磷酸化和 gp130 降解。 MG115 是一种蛋白酶体抑制剂，可抑制这种降解。 OA 的这些作用无法用 PP1 抑制剂互变霉素 (TC) 替代。纯化的 PP2A 在体外对 gp130 的磷酸 Ser-782 进行去磷酸化。将细胞与 OA 预孵育可抑制 IL-6 诱导的 Stat3 激活，表明 OA 通过降解 gp130 阻断 IL-6 信号通路。综上所述，目前的结果强烈表明，gp130 的降解是通过磷酸化-去磷酸化机制进行调节的，其中 PP2A 至关重要，并且 gp130 是癌症的潜在治疗靶点。
The interleukin-6 (IL-6) stimulates growth in cells such as multiple myeloma and B-cell plasmacytomas/hybridomas, while it inhibits growth in several myeloid leukemia cells. The IL-6 receptor has subunit called gp130. It was reported that Ser-782 of gp130 is phosphorylated by unidentified kinase(s) in cell extracts, and level of gp130 (S782A) transiently expressed on the cell surface of COS-7 is 6-times higher than that of the wild type. These results motivated us to analyze whether the phosphorylation of gp130 at Ser-782 is involved in its degradation or not. In this study, we demonstrated here that treatment of HepG2 cells with okadaic acid (OA), a potent inhibitor for PP2A, promotes phosphorylation of gp130 at Ser-782 and degradation of gp130. MG115, a proteasome inhibitor, suppressed this degradation. These effects of OA could not be replaced with tautomycetin (TC), an inhibitor for PP1. Purified PP2A dephosphorylated phospho-Ser-782 of gp130 in vitro. IL-6-induced activation of Stat3 was suppressed by preincubation of the cells with OA, suggesting that the IL-6 signaling pathway was blocked by OA through degradation of gp130. Taken together, present results strongly suggest that degradation of gp130 is regulated through a phosphorylation-dephosphorylation mechanism in which PP2A is crucially involved and that gp130 is a potential therapeutic target in cancers.