Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, Japan.
Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo, Japan.
Biochem Biophys Res Commun. 2014 Feb 14;444(3):360-4. doi: 10.1016/j.bbrc.2014.01.041. Epub 2014 Jan 22.
K-Ras is frequently mutated and activated especially in pancreatic cancers. To analyze K-Ras function, we have searched for K-Ras interacting proteins and found IQ motif containing GTPase activating protein 1 (IQGAP1) as a novel K-Ras binding protein. IQGAP1 has been known as a scaffold protein for B-Raf, MEK1/2 and ERK1/2. Here we showed that IQGAP1 selectively formed a complex with K-Ras but not with H-Ras, and recruited B-Raf to K-Ras. We found that IQ motif region of IQGAP1 interacted with K-Ras. Both active and inactive K-Ras interacted with IQGAP1, and effector domain mutants of K-Ras also associated with IQGAP1, indicating that IQGAP1 interacts with K-Ras irrespective of Ras-effectors like B-Raf. We also found that overexpression or knock-down of IQGAP1 affected the interaction between K-Ras and B-Raf, and IQGAP1 overexpression increased ERK1/2 phosphorylation in K-Ras dependent manner in PANC1 cells. Our data suggest that IQGAP1 has a novel mechanism to modulate K-Ras pathway.
K-Ras 经常发生突变和激活，尤其是在胰腺癌中。为了分析 K-Ras 的功能，我们搜索了与 K-Ras 相互作用的蛋白质，发现含有 IQ 基序的 GTP 酶激活蛋白 1（IQGAP1）是一种新的 K-Ras 结合蛋白。IQGAP1 已被认为是 B-Raf、MEK1/2 和 ERK1/2 的支架蛋白。在这里，我们表明 IQGAP1 选择性地与 K-Ras 形成复合物，而不是与 H-Ras，并且招募 B-Raf 到 K-Ras。我们发现 IQGAP1 的 IQ 基序区域与 K-Ras 相互作用。活性和非活性 K-Ras 都与 IQGAP1 相互作用，并且 K-Ras 的效应器结构域突变体也与 IQGAP1 相关联，表明 IQGAP1 与 K-Ras 相互作用，而与 B-Raf 等 Ras 效应器无关。我们还发现，IQGAP1 的过表达或敲低会影响 K-Ras 和 B-Raf 之间的相互作用，并且 IQGAP1 的过表达以 K-Ras 依赖性方式增加 PANC1 细胞中 ERK1/2 的磷酸化。我们的数据表明 IQGAP1 具有调节 K-Ras 通路的新机制。
