From the Department of Laboratory Medicine, National Institutes of Health, 10 Center Drive, Bethesda, Maryland, 20892, USA.
Sci Rep. 2019 Jul 30;9(1):11057. doi: 10.1038/s41598-019-46677-9.
The Ras family of small GTPases modulates numerous essential processes. Activating Ras mutations result in hyper-activation of selected signaling cascades, which leads to human diseases. The high frequency of Ras mutations in human malignant neoplasms has led to Ras being a desirable chemotherapeutic target. The IQGAP family of scaffold proteins binds to and regulates multiple signaling molecules, including the Rho family GTPases Rac1 and Cdc42. There are conflicting data in the published literature regarding interactions between IQGAP and Ras proteins. Initial reports showed no binding, but subsequent studies claim associations of IQGAP1 and IQGAP3 with K-Ras and H-Ras, respectively. Therefore, we set out to resolve this controversy. Here we demonstrate that neither endogenous IQGAP1 nor endogenous IQGAP3 binds to the major Ras isoforms, namely H-, K-, and N-Ras. Importantly, Ras activation by epidermal growth factor is not altered when IQGAP1 or IQGAP3 proteins are depleted from cells. These data strongly suggest that IQGAP proteins are not functional interactors of H-, K-, or N-Ras and challenge the rationale for targeting the interaction of Ras with IQGAP for the development of therapeutic agents.
Ras 家族的小 GTP 酶调节着许多重要的过程。Ras 激活突变导致特定信号级联的过度激活，从而导致人类疾病。Ras 突变在人类恶性肿瘤中的高频率导致 Ras 成为理想的化疗靶点。IQGAP 家族的支架蛋白与多种信号分子结合并调节其功能，包括 Rho 家族 GTP 酶 Rac1 和 Cdc42。关于 IQGAP 和 Ras 蛋白之间的相互作用，在已发表的文献中有相互矛盾的数据。最初的报告显示没有结合，但随后的研究分别声称 IQGAP1 和 IQGAP3 与 K-Ras 和 H-Ras 相关联。因此，我们着手解决这一争议。在这里，我们证明内源性 IQGAP1 或 IQGAP3 都不会与主要的 Ras 同工型（即 H-、K-和 N-Ras）结合。重要的是，当从细胞中耗尽 IQGAP1 或 IQGAP3 蛋白时，表皮生长因子激活 Ras 的情况并没有改变。这些数据强烈表明 IQGAP 蛋白不是 H-、K-或 N-Ras 的功能相互作用因子，并质疑了针对 Ras 与 IQGAP 相互作用开发治疗剂的合理性。
