Deregulation and Mislocalization of the Cytokinesis Regulator ECT2 Activate the Rho Signaling Pathways Leading to Malignant Transformation

Shin'ichi Saito, Xiu Fen Liu, Keiju Kamijo, Razi Raziuddin, Takashi Tatsumoto, Isamu Okamoto, Xiaoyan Chen, Chong Chou Lee, Matthew V. Lorenzi, Naoya Ohara, Toru Miki

研究成果: ジャーナルへの寄稿学術誌査読

103 被引用数 (Scopus)

抄録

The human ECT2 protooncogene encodes a guanine nucleotide exchange factor for the Rho GTPases and regulates cytokinesis. Although the oncogenic form of ECT2 contains an N-terminal truncation, it is not clear how the structural abnormality of ECT2 causes malignant transformation. Here we show that both the removal of the negative regulatory domain and alteration of subcellular localization are required to induce the oncogenic activity of ECT2. The transforming activity of oncogenic ECT2 was strongly inhibited by dominant negative Rho GTPases, suggesting the involvement of Rho GTPases in ECT2 transformation. Although deletion of the N-terminal cell cycle regulator-related domain (N) of ECT2 did not activate its transforming activity, removal of the small central domain (S), which contains two nuclear localization signals (NLSs), significantly induced the activity. The ECT2 N domain interacted with the catalytic domain and significantly inhibited the focus formation by oncogenic ECT2. Interestingly, the introduction of the NLS mutations in the S domain of N-terminally truncated ECT2 dramatically induced the transforming activity of this otherwise non-oncogenic derivative. Among the known Rho GTPases expressed in NIH 3T3 cells, RhoA was predominantly activated by oncogenic ECT2 in vivo. Therefore, the mislocalization of structurally altered ECT2 might cause the untimely activation of cytoplasmic Rho GTPases leading to the malignant transformation.

本文言語英語
ページ(範囲)7169-7179
ページ数11
ジャーナルJournal of Biological Chemistry
279
8
DOI
出版ステータス出版済み - 2月 20 2004
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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