IQGAP1 in tumorigenesis

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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.