Nucleotide variants within the <i>IQGAP1</i> gene in diffuse‐type gastric cancers

Morris, Leah E.; Bloom, George S.; Frierson, Henry F.; Powell, Steven M.

doi:10.1002/gcc.20150

Cited by 23 publications

(13 citation statements)

References 36 publications

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“…The source of the interaction between APC and IQGAP1 20 relates to cell migration. The two genes have also been associated previously with colorectal cancer 21,25 and directly to CD. 30 More precisely, germline mutations (in which gene APC) cause familial adenomatous polyposis (FAP), which is an autosomal dominant inherited disease characterized by the presence of adenomatous polyps in the colon and rectum, with the inevitable development of colorectal cancer.…”

Section: Discussionmentioning

confidence: 68%

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Using biological networks to search for interacting loci in genome-wide association studies

et al. 2009

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Genome-wide association studies have identified a large number of single-nucleotide polymorphisms (SNPs) that individually predispose to diseases. However, many genetic risk factors remain unaccounted for. Proteins coded by genes interact in the cell, and it is most likely that certain variants mainly affect the phenotype in combination with other variants, termed epistasis. An exhaustive search for epistatic effects is computationally demanding, as several billions of SNP pairs exist for typical genotyping chips. In this study, the experimental knowledge on biological networks is used to narrow the search for two-locus epistasis. We provide evidence that this approach is computationally feasible and statistically powerful. By applying this method to the Wellcome Trust Case -Control Consortium data sets, we report four significant cases of epistasis between unlinked loci, in susceptibility to Crohn's disease, bipolar disorder, hypertension and rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 68%

“…Its role in carcinogenesis has already been reported, 23 and it has been mentioned that IQGPA1 might be involved in gastric and colorectal cancers. 24,25 Figure 1 Overall analysis of the WTCCC data. Quantile -quantile plots of the test statistic observed in the seven studied diseases.…”

Section: Resultsmentioning

confidence: 99%

Using biological networks to search for interacting loci in genome-wide association studies

et al. 2009

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“…A M1231I IQGAP1 mutation was occasionally seen in certain human cancers (29). We examined this mutation in 70 thyroid tumor samples but found only one case (1.4%) to harbor this mutation.…”

Section: Resultsmentioning

confidence: 99%

IQGAP1 Plays an Important Role in the Invasiveness of Thyroid Cancer

Liu

Bojdani

et al. 2010

Clinical Cancer Research

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Purpose: This study was designed to explore the role of IQGAP1 in the invasiveness of thyroid cancer and its potential as a novel prognostic marker and therapeutic target in this cancer.Experimental Design: We examined IQGAP1 copy gain and its relationship with clinicopathologic outcomes of thyroid cancer and investigated its role in cell invasion and molecules involved in the process.Results: We found IQGAP1 copy number (CN) gain !3 in 1 of 30 (3%), 24 of 74 (32%), 44 of 107 (41%), 8 of 16 (50%), and 27 of 41 (66%) of benign thyroid tumor, follicular variant papillary thyroid cancer (FVPTC), follicular thyroid cancer (FTC), tall cell papillary thyroid cancer (PTC), and anaplastic thyroid cancer, respectively, in the increasing order of invasiveness of these tumors. A similar tumor distribution trend of CN !4 was also seen. IQGAP1 copy gain was positively correlated with IQGAP1 protein expression. It was significantly associated with extrathyroidal and vascular invasion of FVPTC and FTC and, remarkably, a 50%-60% rate of multifocality and recurrence of BRAF mutation-positive PTC (P ¼ 0.01 and 0.02, respectively). The siRNA knockdown of IQGAP1 dramatically inhibited thyroid cancer cell invasion and colony formation. Coimmunoprecipitation assay showed direct interaction of IQGAP1 with E-cadherin, a known invasion-suppressing molecule, which was upregulated when IQGAP1 was knocked down. This provided a mechanism for the invasive role of IQGAP1 in thyroid cancer. In contrast, IQGAP3 lacked all these functions.Conclusions: IQGAP1, through genetic copy gain, plays an important role in the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer. Clin Cancer Res; 16(24); 6009-18. Ó2010 AACR.

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“…A recent study found that 2 of 33 diffuse type gastric cancer samples contained a mutation in codon 1231 of the GRD (43). This mutation converts the native methionine to an isoleucine.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure of the GTPase-activating Protein-related Domain from IQGAP1

Kurella

Richard

Parke

et al. 2009

Journal of Biological Chemistry

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IQGAP1 is a 190-kDa molecular scaffold containing several domains required for interaction with numerous proteins. One domain is homologous to Ras GTPase-activating protein (GAP) domains. However, instead of accelerating hydrolysis of bound GTP on Ras IQGAP1, using its GAP-related domain (GRD) binds to Cdc42 and Rac1 and stabilizes their GTP-bound states. We report here the crystal structure of the isolated IQGAP1 GRD. Despite low sequence conservation, the overall structure of the GRD is very similar to the GAP domains from p120 RasGAP, neurofibromin, and SynGAP. However, instead of the catalytic "arginine finger" seen in functional Ras GAPs, the GRD has a conserved threonine residue. GRD residues 1099 -1129 have no structural equivalent in RasGAP and are seen to form an extension at one end of the molecule. Because the sequence of these residues is highly conserved, this region likely confers a functionality particular to IQGAP family GRDs. We have used isothermal titration calorimetry to demonstrate that the isolated GRD binds to active Cdc42. Assuming a mode of interaction similar to that displayed in the Ras-RasGAP complex, we created an energy-minimized model of Cdc42⅐GTP bound to the GRD. Residues of the GRD that contact Cdc42 map to the surface of the GRD that displays the highest level of sequence conservation. The model indicates that steric clash between threonine 1046 with the phosphate-binding loop and other subtle changes would likely disrupt the proper geometry required for GTP hydrolysis.The small GTPase Ras functions as a binary switch in cell signaling processes. When bound to GTP, Ras is able to interact with effector proteins, including Raf kinase, and alter their activities. Ras signaling is terminated when bound GTP is hydrolyzed to GDP and inorganic phosphate. The basal rate of GTP hydrolysis on Ras is quite slow (ϳ1.2 ϫ 10 Ϫ4 s Ϫ1), but this rate of hydrolysis can be enhanced ϳ10 5 -fold by interaction with a GTPase-activating protein (GAP) 2 (1). Several RasGAPs have been identified to date including p120 RasGAP and neurofibromin (NF1). The Rho family of Ras-related small GTPases also function as binary switches in cell signaling processes. Whereas the intrinsic rate of GTP hydrolysis on Rho proteins is faster than Ras, this rate can also be stimulated by interaction with a RhoGAP. Examination of the structures of the GAP domains of p120RasGAP (2), neurofibromin (3), SynGAP (4), and the GAP domains from the RhoGAPs p50 RhoGAP and the Bcr homology domain of phosphatidylinositol 3-kinase (5, 6) indicates that although ostensibly different, these all-helical domains are structurally related (7).IQGAP1 was discovered by chance during an attempt to isolate novel matrix metalloproteinases (8). Analysis reveals that the protein contains several discrete domains and motifs including a region containing four isoleucine-and glutaminerich motifs (IQ repeats) and a region with sequence homology to the Ras-specific GAP domains of p120RasGAP, NF1, and

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Nucleotide variants within the IQGAP1 gene in diffuse‐type gastric cancers

Cited by 23 publications

References 36 publications

Using biological networks to search for interacting loci in genome-wide association studies

Using biological networks to search for interacting loci in genome-wide association studies

IQGAP1 Plays an Important Role in the Invasiveness of Thyroid Cancer

Crystal Structure of the GTPase-activating Protein-related Domain from IQGAP1

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