Multiple proteins mediate IQGAP1-stimulated cell migration

Mataraza, Jennifer; Li, Zhigang; Jeong, Ha‐Won; Brown, Matthew; Sacks, David B.

doi:10.1016/j.cellsig.2007.04.011

Cited by 31 publications

(31 citation statements)

References 44 publications

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“…IQGAP1G75Q, a point mutant construct that cannot bind actin, does not increase cell motility (28). Concordant with these observations, we observe here that IQGAP1G75Q fails to increase cell invasion.…”

Section: Discussionsupporting

confidence: 89%

“…The construction of IQGAP1⌬GRD, IQGAP1G75Q and IQGAP1⌬MK24 has been described previously (27)(28)(29). Myc-tagged forms of the dominant negative constructs N17Cdc42 and N17Rac1 (30) were kindly provided by Alan Hall (University College London).…”

Section: Methodsmentioning

confidence: 99%

“…We used mutant IQGAP1 constructs to gain further insight into which binding partners are necessary for IQGAP1 to enhance cell invasion. IQGAP1G75Q, a point mutant that lacks binding to actin (28), and IQGAP1⌬MK24, which is unable to bind Cdc42 or Rac1 (29), were used. Transient overexpression of wild type IQGAP1 increases cell invasion, by ϳ2.5-fold (Fig.…”

Section: Altering Iqgap1 Concentration In Mcf-7 Cells Alters the Amoumentioning

confidence: 99%

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IQGAP1 Stimulates Proliferation and Enhances Tumorigenesis of Human Breast Epithelial Cells

Jadeski

Mataraza

Jeong

et al. 2008

Journal of Biological Chemistry

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129

143

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The scaffold protein IQGAP1 integrates signaling pathways and participates in diverse cellular activities. IQGAP1 is overexpressed in a number of human solid neoplasms, but its functional role in tumorigenesis has not been previously evaluated. Here we report that IQGAP1 contributes to neoplastic transformation of human breast epithelial cells. The amount of IQGAP1 in breast carcinoma is greater than that in normal tissue, with highly metastatic breast epithelial cells expressing the highest levels. Overexpression of IQGAP1 enhances proliferation of MCF-7 breast epithelial cells. Reduction of endogenous IQGAP1 by RNA interference impairs both serum-dependent and anchorage-independent growth of MCF-7 cells. Consistent with these in vitro observations, immortalized MCF-7 cells overexpressing IQGAP1 form invasive tumors in immunocompromised mice, whereas tumors derived from MCF-7 cells with stable knockdown of IQGAP1 are smaller and less invasive. In vitro analysis with selected IQGAP1 mutant constructs and a chemical inhibitor suggests that actin, Cdc42/Rac1, and the mitogen-activated protein kinase pathway contribute to the mechanism by which IQGAP1 increases cell invasion. Collectively, our data reveal that IQGAP1 enhances mammary tumorigenesis, suggesting that it may be a target for therapeutic intervention.Tumor progression that culminates in clinically relevant metastatic lesions is the end point of a complex sequence of interrelated cellular events. After the initial transforming event, tumor cell proliferation, invasion, and migration, as well as vascularization of the tumor mass, occur. A thorough understanding of the molecular mechanisms that regulate tumor progression will provide the biological foundation for improving the efficacy of current therapeutic interventions (1-3).IQGAP1 is a 189-kDa scaffolding protein that contains multiple protein-interacting domains (for reviews see Refs. 4 -7). These include a calponin homology domain, a polyprolinebinding domain, four calmodulin-binding motifs, and a Ras-GAP-related domain. The motifs present in IQGAP1 are involved in the interaction of IQGAP1 with specific proteins, such as actin, calmodulin, members of the Rho GTPase family (i.e. Rac1 and Cdc42), Rap1, E-cadherin, ␤-catenin, members of the mitogen-activated protein kinase (MAPK) 4 pathway, and adenomatous polyposis coli (7,8). By interacting with these proteins, IQGAP1 regulates multiple fundamental cellular activities including cytoskeletal organization, cell-cell adhesion, cell migration, transcription, and signal transduction. For example, binding of IQGAP1 to ␤-catenin both disrupts the E-cadherin-catenin complex, inhibiting epithelial cell-cell adhesion (9), and increases ␤-catenin-mediated transcriptional activation (10). IQGAP1 increases active Cdc42 in mammalian cells, resulting in formation of actin filopodia and microspikes (11), and promotion of cell migration and invasion (12). These morphological and functional changes are not observed with a mutant IQGAP1 construct with impeded Cdc42-me...

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Altering Iqgap1 Concentration In Mcf-7 Cells Alters the Amoumentioning

confidence: 99%

See 1 more Smart Citation

IQGAP1 Stimulates Proliferation and Enhances Tumorigenesis of Human Breast Epithelial Cells

Jadeski

Mataraza

Jeong

et al. 2008

Journal of Biological Chemistry

Self Cite

129

143

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“…CyclinD3 expression is clinically correlated with distant metastasis (19). IQGAP1 has been shown to promote tumor cell motility in cancer metastasis (29). Its expression is up-regulated in colorectal carcinomas and is associated with invasion fronts (30).…”

Section: Discussionmentioning

confidence: 99%

Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis

Sun

Guo

et al. 2009

Clinical Cancer Research

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Purpose: This study aimed to identify novel biological markers for the prediction of colorectal cancer liver metastasis. Experimental Design: We established two models that mimicked the interactions between colorectal tumor cells and the liver microenvironment. From these models we established subcell lines that had an enhanced ability to metastasize to the liver. Genes that related to hepatic metastasis were screened by microarray. The candidate markers were tested by immunohistochemistry, and their predictive accuracy was assessed by the cross-validation method and an independent test set. Results: Highly metastatic colon cancer cell sublines SW1116p21 and SW1116v3 were established from the tumor cell-microenvironment interaction models. Seven of the upregulated genes in the sublines were selected as candidate markers for predicting metastatic potential. A total of 245 colorectal cancer samples were divided into a training set containing 117 cases and a test set containing 128 cases. In the training set, immunohistochemical analysis showed CCL2 and SNCG expression was higher in the hepatic metastasis group than in the nonmetastasis group, and was correlated with poor survival. Logistic regression analysis revealed that CCL2 and SNCG levels in primary tumors, serum carcinoembryonic antigen level, and lymph node metastasis status were the only significant (P < 0.05) parameters for detecting liver metastasis. In leave-one-out-cross-validation, the two markers, when combined with clinicopathologic features, resulted in 90.5% sensitivity and 90.7% specificity for hepatic metastasis detection. In an independent test set, the combination achieved 87.5% sensitivity and 82% specificity for predicting the future hepatic metastasis of colorectal cancer. Conclusion: Our results suggest that these models are able to mimic the interactions between colorectal cancer cells and the liver microenvironment, and may represent a promising strategy to identify metastasis-related genes. CCL2 and SNCG, combined with clinicopathologic features, may be used as accurate predictors of liver metastasis in colorectal cancer. (Clin Cancer Res 2009;15(17):5485-93) Colorectal carcinoma is one of the major causes of cancer death worldwide (1). Liver is the most common target for metastasis in patients with this disease. It is estimated that approximately 50% of colorectal cancer patients develop liver metastases, with 15% to 25% of synchronous and 20% of heterochronous cases (2). Liver metastasis is the most critical prognostic factor for colorectal cancer. The 5-year overall survival rate of patients with hepatic metastasis is only 25% to 40%

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“…The mutant constructs used were IQGAP1⌬GRD, which is a dominant negative that decreases the amount of GTP-bound Cdc42 and Rac1 in cells (24,25), IQGAP1⌬MK24, which neither binds Rac1 nor Cdc42 nor increases GTP-Cdc42 levels in cells (26), and IQGAP1G75Q, a point mutant that does not bind to actin but binds Cdc42 and Rac1 indistinguishably from wild type IQGAP1 (27). These mutant constructs, all tagged with GFP, were expressed in HeLa cells and compared with GFP-tagged wild type IQGAP1.…”

Section: Iqgap1 Associates With Actin To Localize To Sites Of Salmonementioning

confidence: 99%

IQGAP1 Regulates Salmonella Invasion through Interactions with Actin, Rac1, and Cdc42

Brown

Bry

et al. 2007

Journal of Biological Chemistry

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To infect host cells, Salmonella utilizes an intricate system to manipulate the actin cytoskeleton and promote bacterial uptake. Proteins injected into the host cell by Salmonella activate the Rho GTPases, Rac1 and Cdc42, to induce actin polymerization. Following uptake, a different set of proteins inactivates Rac1 and Cdc42, returning the cytoskeleton to normal. Although the signaling pathways allowing Salmonella to invade host cells are beginning to be understood, many of the contributing factors remain to be elucidated. IQGAP1 is a multidomain protein that influences numerous cellular functions, including modulation of Rac1/Cdc42 signaling and actin polymerization. Here, we report that IQGAP1 regulates Salmonella invasion. Through its interaction with actin, IQGAP1 co-localizes with Rac1, Cdc42, and actin at sites of bacterial uptake, whereas infection promotes the interaction of IQGAP1 with both Rac1 and Cdc42. Knockdown of IQGAP1 significantly reduces Salmonella invasion and abrogates activation of Cdc42 and Rac1 by Salmonella. Overexpression of IQGAP1 significantly increases the ability of Salmonella to enter host cells and required interaction with both actin and Cdc42/Rac1. Together, these data identify IQGAP1 as a novel regulator of Salmonella invasion.Salmonella continues to be a major cause of morbidity and mortality worldwide, causing food poisoning and typhoid fever. Using a highly intricate system, Salmonella is able to hijack the actin regulatory machinery of the host cell to promote bacterial entry. To do this, Salmonella uses a type III secretion system to inject a battery of effector proteins into the host cell (reviewed in Ref. 1). These proteins are able to mimic host cell activators of actin polymerization, resulting in membrane ruffling and macropinocytosis (2). Key to these processes are three Salmonella effector proteins, SopE, SopE2, and SopB. SopE and SopE2 bind to and activate Rac1 and Cdc42 (3, 4). Despite sharing very little sequence similarity, SopE/SopE2 and eukaryotic cell guanosine nucleotide exchange factors (GEFs) 2 use nearly identical catalytic mechanisms to activate Rac1 and Cdc42. SopB, a phosphoinositide phosphatase (5, 6), indirectly regulates actin polymerization through the activation of SH3-containing GEF and RhoG (7). IQGAP1 is a multidomain protein that binds many targets, including Cdc42 (8 -10), Rac1 (8, 11), actin (12, 13), calmodulin (10, 12), Rap1 (14), and components of the mitogen-activated protein (MAP) kinase cascade (15-17) (reviewed in Refs. 18 -21). A primary function of IQGAP1 is to modulate cytoskeletal architecture. IQGAP1 enhances actin polymerization in vitro (22, 23) and co-localizes with actin in lamellipodia (8). In addition to a direct interaction with actin, IQGAP1 modulates the cytoskeleton indirectly through the Rho GTPases (18). IQGAP1 preferentially binds to active (GTP-bound) Cdc42 (8, 10) and Rac1 (8). IQGAP1 is not a GTPase-activating protein (GAP) and actually inhibits the intrinsic GTPase activity of Cdc42 in vitro, stabilizing Cdc42 in...

show abstract

Multiple proteins mediate IQGAP1-stimulated cell migration

Cited by 31 publications

References 44 publications

IQGAP1 Stimulates Proliferation and Enhances Tumorigenesis of Human Breast Epithelial Cells

IQGAP1 Stimulates Proliferation and Enhances Tumorigenesis of Human Breast Epithelial Cells

Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis

IQGAP1 Regulates Salmonella Invasion through Interactions with Actin, Rac1, and Cdc42

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