IQGAP1 in tumorigenesis

在本财年，我们完成了以下工作： 1.鼠伤寒沙门氏菌侵占支架蛋白IQGAP1，操控rac1和MAPK(丝裂原活化蛋白激酶)信号转导。这些观察结果促进了我们对沙门氏菌如何重新排列宿主细胞骨架以侵袭细胞的理解，并提示IQGAP1可能是沙门氏菌致病的潜在治疗靶点。 2.发现蛋白激酶A锚定蛋白AKAP220与细胞骨架支架蛋白IQGAP1相互作用。AKAP220/IQGAP1网络接收并整合钙和cAMP第二信使信号，从而组织影响细胞迁移的信号元件。这些发现提供了对癌细胞侵袭和转移过程中细胞骨架极化的洞察。 3.证实钙结合蛋白CaM与人雌激素受体(ER)结合。核磁共振光谱的详细结构分析得出了一个令人惊讶的发现，即一个钙调蛋白与两个内质网分子结合。因此，在没有雌激素的情况下，钙调蛋白有助于内质网的二聚化。这些数据加深了我们对钙调蛋白调节ER介导的转录激活的机制的理解，并可能对乳腺癌的治疗有一定的意义。 4.结果表明，IQGAP1通过破坏黏附连接促进大肠杆菌K1侵袭脑内皮细胞。这些发现为了解大肠杆菌破坏紧密连接从而导致新生儿脑膜炎脑水肿的分子机制提供了洞察力。 5.鉴定核因子-红系相关因子2(Nrf2)为IQGAP1的结合伙伴。Nrf2是调节细胞对氧化应激防御的关键转录因子。对相互作用的功能分析表明，IQGAP1在Nrf2的稳定和反式激活中起着关键作用。综上所述，这些数据表明IQGAP1可能有助于Nrf2对抗氧化酶的调节。

During the fiscal year we accomplished the following: 1. Documented that Salmonella enterica serotype Typhimurium usurps the scaffold protein IQGAP1 to manipulate Rac1 and MAPK (mitogen-activated protein kinase) signaling. These observations promote our understanding of how Salmonella re-arranges the host-cell cytoskeleton to invade cells and suggest that IQGAP1 may be a potential therapeutic target for Salmonella pathogenesis. 2. Discovered that the protein kinase A anchoring protein AKAP220 interacts with the cytoskeletal scaffolding protein IQGAP1. AKAP220/IQGAP1 networks receive and integrate calcium and cAMP second messenger signals, thus organizing signaling elements that impact cell migration. The findings provide insight into cytoskeletal polarization during invasion and metastasis of cancer cells. 3. Demonstrated that the calcium-binding protein calmodulin binds the human estrogen receptor (ER). Detailed structural analysis by nuclear magnetic resonance spectroscopy yielded the surprising finding that a single calmodulin binds two molecules of ER. Thus, calmodulin facilitates dimerization of ER in the absence of the hormone estrogen. These data enhance our comprehension of the mechanism by which calmodulin regulates ER-mediated transcriptional activation and may have implications in the treatment of breast carcinoma. 4. Showed that IQGAP1 mediates the disruption of adherens junctions to promote Escherichia coli K1 invasion of brain endothelial cells. These findings provide insight into the molecular mechanism by which E. coli disrupts tight junctions, thereby leading to brain edema in neonatal meningitis. 5. Identified nuclear factor-erythroid-related factor 2 (Nrf2) as a binding partner of IQGAP1. Nrf2 is a critical transcriptional factor in regulating cellular defense against oxidative stress. Functional analysis of the interaction revealed a critical role for IQGAP1 in the stability and transactivation of Nrf2. Collectively, these data suggest that IQGAP1 may contribute to regulation of antioxidant enzymes by Nrf2.