IQGAP1 is a 190kD cytosolic protein scaffold that possesses several protein-protein interaction domains. The results of recent research link IQGAP1 to numerous proteins including growth factor receptors, MAP kinase signaling components, and cell junction proteins. Although the details are not well understood, through diverse interactions IQGAP1 has an important role in numerous processes including the definition of cell polarity, directed cell migration, and cell invasion. There is a growing body of circumstantial evidence that IQGAP1 is involved in carcinogenesis, and IQGAP1 is overexpressed in several different neoplasms. Among other intriguing observations, over-expression of IQGAP1 has been shown to destabilize cadherin-based cell-cell junctions and increase cell motility and invasiveness in a Rac1/Cdc42-dependent manner. Currently, there is very little structural information for IQGAP1 and its protein-protein interactions. However, several observations imply that IQGAP1 is not a passive scaffold that merely collects signaling components. First, the oligomerization of IQGAP1 is required for normal function. Second, IQGAP1 is a novel effector of the Rho-family GTPases Rac1 and Cdc42 and binding of activated Cdc42 enhances dimer formation and modulates interactions mediated by the IQGAP1 C-terminus. Third, a mutation that introduces 17 residues within the IQGAP1 GAP-related domain (GRD) confers a "constitutively-active" phenotype;IQGAP1 molecules that behave as though bound to active Cdc42. The 17 residue insertion is located on the surface of the GRD that would bind GTPases if the mode of binding is similar to the Ras?RasGAP interaction. Lastly, IQGAP1 amino terminal residues inhibit in trans the interaction between the IQGAP1 C-terminus and N-WASP. Based on these and other observations, we believe that through diverse inter- and intramolecular interactions, IQGAP1 exposes and conceals binding determinants necessary for the regulation of its functions. The focus of this proposal is to elucidate the IQGAP1 tertiary structure and the structural requirements for IQGAP1's interactions with binding partners.
IQGAP1, a large molecular scaffold that interacts with numerous cellular proteins, is over-expressed in some cancers, and has been shown to increase cell motility and invasive potential, and to regulate cell-cell interactions. These observations are consistent with the notion that IQGAP1 activity may be required for cancer cells to leave a primary tumor and invade distant tissues. This proposal is designed to provide much needed structural information as it pertains to IQGAP1 function.
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