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IQGAP3 regulates cell proliferation through the Ras/ERK signalling cascade

Nature Cell Biology volume 10, pages 971–978 (2008)Cite this article

Abstract

Proliferation of epithelial cells must be spatiotemporally regulated to maintain the organization of epithelial sheets. Here we show that the IQGAP family, comprising IQGAP1, 2 and 3, underlies lateral cell–cell contacts of epithelial cells. Of the three proteins, IQGAP3 is unique in that its expression is specifically confined to proliferating cells. Knockdown of IQGAP3 in cultured epithelial cells caused inhibition of proliferation and ERK activity. When exogenously expressed in quiescent cells, IQGAP3 was capable of inducing cell-cycle re-entry, which was completely inhibited by the MEK inhibitor U0126. Thus, IQGAP3 is necessary and sufficient for driving cell proliferation and ERK acts downstream of IQGAP3. Furthermore, IQGAP3 specifically interacted with the active, GTP-bound form of Ras, and in IQGAP3 knockdown cells, the activity of Ras, but not of other small GTPases, was inhibited. Thus, IQGAP3 regulates the promotion of cell proliferation through Ras-dependent ERK activation.

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Figure 1: Specific expression of IQGAP3 in proliferating cells.
Figure 2: Stable knockdown of IQGAP3 expression in Eph4 cells.
Figure 3: IQGAP3-induced cell cycle re-entry.
Figure 4: Specific interaction of IQGAP3 with Ras.
Figure 5: Specific downregulation of Ras in IQGAP3-KD cells.

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Acknowledgements

We would like to thank T. Noda, S. Nishikawa and our laboratory members for discussion and encouragement during this study. Especially, we thank C. Inoue for her excellent technical assistance. We also thank D. Sipp for editing English in the native speaker level. This study was supported in part by a Grant-in-Aid for Cancer Research to Sh. Tsukita and Sa. Tsukita and by a Grant-in-Aid for Creative Scientific Research from the Ministry of Education, Science and Culture of Japan to Sa. Tsukita.

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Author notes

  1. Hisashi Nojima and Makoto Adachi: These authors contributed equally to this work.

  2. Shoichiro Tsukita: Deceased

Authors and Affiliations

  1. Laboratory of Biological Science, Graduate School of Frontier Biosciences/Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan

    Hisashi Nojima, Takeshi Matsui & Sachiko Tsukita

  2. Department of Cell Biology,

    Makoto Adachi & Shoichiro Tsukita

  3. Frontier Technology Center, Faculty of Medicine, Kyoto University, Sakyo-ku, 606-8501, Kyoto, Japan

    Katsuya Okawa

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  1. Hisashi Nojima
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Correspondence to Sachiko Tsukita.

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Nojima, H., Adachi, M., Matsui, T. et al. IQGAP3 regulates cell proliferation through the Ras/ERK signalling cascade. Nat Cell Biol 10, 971–978 (2008). https://doi.org/10.1038/ncb1757

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