State Key Laboratory of Infectious Disease Diagnosis and Treatment First Affiliated Hospital, College of Medicine, Zhejiang University.
Exp Mol Med. 2010 Jul 31;42(7):477-83. doi: 10.3858/emm.2010.42.7.049.
The scaffold protein IQGAP1 shows elevated levels in several cancer types, but its expression in hepatocellular carcinoma is unknown. We found that 58% of human hepatocellular carcinoma tissue samples had increased IQGAP1 expression compared to adjacent normal tissue. Overexpressing IQGAP1 raised the in vivo tumorigenicity of hepatocellular carcinoma cells, and forced overexpression of IQGAP1 in vitro stimulated cell proliferation. Cell growth was reduced by knockdown or mutation of IQGAP1, or by treatment of cells with a phosphotidylinositol 3-kinase inhibitor. To determine the mechanism by which IQGAP1 overexpression affected hepatocellular carcinoma cells, we confirmed its interaction in these cells with mammalian target of rapamycin (mTOR), a serine/threonine kinase that integrates signals about nutrient and energy status with downstream effectors that influence cell division. In addition, we discovered a new interaction involving IQGAP1, mTOR and Akt, which is a downstream target of mTOR. Akt phosphorylation on Ser-473, which is catalyzed by mTOR and required for Akt activation, increased with increasing amounts of IQGAP1, and decreased with IQGAP1 mutation. We hypothesize that IQGAP1 is a scaffold that facilitates mTOR and Akt interaction.
支架蛋白 IQGAP1 在几种癌症类型中表达水平升高，但在肝细胞癌中的表达情况尚不清楚。我们发现，与相邻的正常组织相比，58%的人肝细胞癌组织样本中 IQGAP1 的表达增加。过表达 IQGAP1 提高了肝细胞癌细胞的体内致瘤性，体外强制过表达 IQGAP1 刺激细胞增殖。IQGAP1 的敲低或突变，或用磷酸肌醇 3-激酶抑制剂处理细胞，均降低了细胞生长。为了确定 IQGAP1 过表达影响肝细胞癌细胞的机制，我们在这些细胞中证实了其与哺乳动物雷帕霉素靶蛋白（mTOR）的相互作用，mTOR 是一种丝氨酸/苏氨酸激酶，它将有关营养和能量状态的信号与影响细胞分裂的下游效应物整合在一起。此外，我们发现了涉及 IQGAP1、mTOR 和 Akt 的新相互作用，Akt 是 mTOR 的下游靶标。由 mTOR 催化的 Akt 在 Ser-473 上的磷酸化是 Akt 激活所必需的，随着 IQGAP1 数量的增加而增加，随着 IQGAP1 突变而减少。我们假设 IQGAP1 是一种支架，促进了 mTOR 和 Akt 的相互作用。
