IQGAP1 in tumorigenesis

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Abstract

During the fiscal year we accomplished the following: 1. The secreted signaling protein Wnt5a promotes the formation of the Wnt-receptor-actin-myosin-polarity (WRAMP) structure, which coordinates retraction at the trailing edge. We demonstrated that WRAMP assembly requires an interaction between IQGAP1 and the transmembrane protein melanoma cell adhesion molecule (MCAM) in melanoma cells. Once assembled, WRAMP coordinates several processes that promote membrane retraction, including Ca2+ release from the endoplasmic reticulum at the rear of the cell. Ca2+ both activates the protease calpain, which cleaves proteins at the trailing edge, and facilitates actomyosin contraction, leading to membrane retraction. These findings indicate that IQGAP1 operates at the trailing edge of migrating cells. 2. Demonstrated that the scaffold protein IQGAP1 directly binds the human estrogen receptors ERα and ERβ. Investigation with multiple short fragments of the proteins showed that ERα binds to the IQ domain of IQGAP1, whereas the hinge region of ERα is responsible for binding IQGAP1. In addition, IQGAP1 and ERα co-immunoprecipitated from cells, and the association was modulated by estradiol.. Knockdown of endogenous IQGAP1 attenuated the ability of estradiol to induce transcription of the estrogen-responsive genes pS2, progesterone receptor, and cyclin D1. These data reveal that IQGAP1 binds to ERα and modulates its transcriptional function, suggesting that IQGAP1 might be a target for therapy in patients with breast carcinoma. 3. Hepatocyte growth factor (HGF) activates the receptor tyrosine kinase, c-MET, which regulates the cytoskeleton and cell-cell contacts. HGF stimulation strengthens barrier function in some cell types, e.g., endothelial cells. We showed that siRNA knockdown of IQGAP1 or Rac1 attenuated HGF-induced increase in endothelial barrier. Investigation into the mechanism revealed that HGF induced the formation of a Rac-1 dependent complex containing IQGAP1, EB1 and cortactin. Cortactin promotes actin polymerization, and the complex is necessary for cortical actin remodeling and peripheral microtubule growth that are required for strengthening barrier functions. These findings indicate that IQGAP1 functions as a scaffold between actin and microtubules to promote enhanced barrier functions downstream of HGF. 4. In some tissues, HGF promotes disassembly of cell-cell adhesions and cell migration. For example, HGF induces colony escape of DU145 prostate cancer and HT29 colon cancer cells. We demonstrated that this effect is mediated by a complex between IQGAP1, E-cadherin and PAK6 (p-21 activated 6), a kinase that is often overexpressed in cancers. IQGAP1 promotes activation of PAK6, which then phosphorylates β-catenin, a component of cell-cell junctions, to mediate junction disassembly. These data suggest that the interaction between IQGAP1 and PAK6 may contribute to cancer metastasis.