Nojima Hisashi, Adachi Makoto, Matsui Takeshi, Okawa Katsuya, Tsukita Shoichiro, Tsukita Sachiko
Laboratory of Biological Science, Graduate School of Frontier Biosciences/Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Nat Cell Biol. 2008 Aug;10(8):971-8. doi: 10.1038/ncb1757. Epub 2008 Jul 6.
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.
上皮细胞的增殖必须在时空上受到调控，以维持上皮细胞层的组织结构。在此我们表明，由IQGAP1、2和3组成的IQGAP家族是上皮细胞侧向细胞间接触的基础。在这三种蛋白质中，IQGAP3的独特之处在于其表达特异性地局限于增殖细胞。在培养的上皮细胞中敲低IQGAP3会导致增殖抑制和ERK活性降低。当在静止细胞中外源表达时，IQGAP3能够诱导细胞周期重新进入，而这被MEK抑制剂U0126完全抑制。因此，IQGAP3对于驱动细胞增殖是必要且充分的，并且ERK在IQGAP3的下游发挥作用。此外，IQGAP3特异性地与活性的、GTP结合形式的Ras相互作用，并且在IQGAP3敲低的细胞中，Ras的活性受到抑制，而其他小GTP酶的活性不受影响。因此，IQGAP3通过Ras依赖的ERK激活来调节细胞增殖的促进作用。
