Institute for Biotechnology and Life Sciences, Cornell University, Ithaca, NY 14853-2703, USA.
J Cell Sci. 2012 Apr 15;125(Pt 8):2041-52. doi: 10.1242/jcs.098947. Epub 2012 Feb 10.
Defining the mechanisms that control cell growth and division is crucial to understanding cell homeostasis, which impacts human diseases such as cancer and diabetes. IQGAP1, a widely conserved effector and/or regulator of the GTPase CDC42, is a putative oncoprotein that controls cell proliferation; however, its mechanism in tumorigenesis is unknown. The mechanistic target of rapamycin (mTOR) pathway, the center of cell growth control, is commonly activated in human cancers, but has proved to be an ineffective clinical target because of an incomplete understanding of its mechanisms in cell growth inhibition. Using complementary studies in yeast and mammalian cells, we examined a potential role for IQGAP1 in regulating the negative feedback loop (NFL) of mTOR complex 1 (mTORC1) that controls cell growth. Two-hybrid screens identified the yeast TORC1-specific subunit Tco89p as an Iqg1p-binding partner, sharing roles in rapamycin-sensitive growth, axial-bud-site selection and cytokinesis, thus coupling cell growth and division. Mammalian IQGAP1 binds mTORC1 and Akt1 and in response to epidermal growth factor (EGF), cells expressing the mTORC1-Akt1-binding region (IQGAP1(IR-WW)) contained attenuated phosphorylated ERK1/2 (ERK1/2-P) activity and inactive glycogen synthase kinase 3α/β (GSK3α/β), which control apoptosis. Interestingly, these cells displayed a high level of Akt1 S473-P, but an attenuated level of the mTORC1-dependent kinase S6K1 T389-P and induced mTORC1-Akt1- and EGF-dependent transformed phenotypes. Moreover, IQGAP1 appears to influence cell abscission and its activity is elevated in carcinoma cell lines. These findings support the hypothesis that IQGAP1 acts upstream on the mTORC1-S6K1→Akt1 NFL and downstream of it, to couple cell growth and division, and thus like a rheostat, regulates cell homeostasis, dysregulation of which leads to tumorigenesis or other diseases. These results could have implications for the development of the next generation of anticancer therapeutics.
定义控制细胞生长和分裂的机制对于理解细胞内稳态至关重要，而细胞内稳态会影响癌症和糖尿病等人类疾病。IQGAP1 是 CDC42 GTPase 的广泛保守效应物和/或调节剂，是一种潜在的癌蛋白，可控制细胞增殖；然而，其在肿瘤发生中的机制尚不清楚。雷帕霉素（mTOR）途径是细胞生长控制的中心，在人类癌症中通常被激活，但由于对其在细胞生长抑制中的机制缺乏了解，因此被证明是一个无效的临床靶点。通过在酵母和哺乳动物细胞中进行互补研究，我们研究了 IQGAP1 在调节 mTOR 复合物 1（mTORC1）负反馈回路（NFL）中的潜在作用，该反馈回路控制细胞生长。双杂交筛选鉴定出酵母 TORC1 特异性亚基 Tco89p 是 Iqg1p 的结合伴侣，在雷帕霉素敏感的生长、轴突芽位点选择和胞质分裂中发挥作用，从而将细胞生长和分裂偶联。哺乳动物 IQGAP1 与 mTORC1 和 Akt1 结合，并且响应表皮生长因子（EGF），表达 mTORC1-Akt1 结合区域（IQGAP1(IR-WW)）的细胞显示出减弱的磷酸化 ERK1/2（ERK1/2-P）活性和失活的糖原合酶激酶 3α/β（GSK3α/β），这两者控制细胞凋亡。有趣的是，这些细胞显示出 Akt1 S473-P 的高水平，但 mTORC1 依赖性激酶 S6K1 T389-P 的水平减弱，并诱导 mTORC1-Akt1-和 EGF-依赖性转化表型。此外，IQGAP1 似乎影响细胞分离，并且其活性在癌细胞系中升高。这些发现支持以下假设：IQGAP1 在 mTORC1-S6K1→Akt1 NFL 的上游起作用，并且在其下游起作用，以偶联细胞生长和分裂，因此就像变阻器一样，调节细胞内稳态，其失调会导致肿瘤发生或其他疾病。这些结果可能对下一代抗癌治疗药物的开发具有重要意义。
