Cdc42 and Rac1 Regulate the Interaction of IQGAP1 with β-Catenin

Fukata, Masaki; Kuroda, Shinya; Nakagawa, Masato; Kawajiri, Aie; Itoh, Naohiro; Shoji, Ikuo; Matsuura, Yoshiharu; Yonehara, Shin; Fujisawa, Hajime; Kikuchi, Akira; Kaibuchi, Kozo

doi:10.1074/jbc.274.37.26044

Cited by 212 publications

(175 citation statements)

References 41 publications

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“…In its activated GTPbound form, Rac1 sequesters IQGAP1 and prevents its binding to b-catenin, thereby stabilizing cadherin-mediated cell adhesion. 24 The role of IQGAP1 in gastric carcinogenesis has been studied by several other groups, but to our knowledge, data on the prognostic significance of IQGAP1 in gastric cancer has not been reported. An inverse correlation of IQGAP1 with intercellular adhesion was shown in gastric cancers with cytoplasmic localization of IQGAP1 in intestinal type gastric cancer and membranous localization of IQGAP1 at the cellular membrane in diffuse type gastric cancer cells without cell-cell contact.…”

Section: The Rac1 Downstream Effector Iqgap1mentioning

confidence: 96%

Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer

et al. 2008

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Rho GTPases are a family of major regulators of E-cadherin-mediated cell adhesion that are implicated in the carcinogenic process by deregulated expression of the family members itself or of upstream modulators or downstream effectors. Combined investigation of the Rho GTPase Rac1, the effector protein IQGAP1 and the activator Tiam1 in relation to expression or mutation of E-cadherin in gastric adenocarcinomas has not been reported. The aim of the study was to determine the expression and prognostic significance of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric adenocarcinomas. Gastric carcinomas of 76 patients were investigated immunohistochemically in a tissue microarray study for expression of Rac1, IQGAP1, Tiam1 and E-cadherin. Correlations with clinical and follow-up data were examined. Moderate or strong reactivity for Rac1 was observed in 46% and for Tiam1 in 56% of tumors. Expression of IQGAP1 was present in 59% and of E-cadherin in 87% of tumors. While Rac1 and E-cadherin expression were not related to prognosis, a trend was observed between a lack of IQGAP1 expression (log-rank 0.088) as well as presence of Tiam1 (log-rank 0.097) and favorable prognosis in Kaplan-Meier survival analysis. Expression of Rac1 was positively linked to IQGAP1 expression (P ¼ 0.007, r ¼ 0.343) and tended to be inversely associated with expression of E-cadherin (P ¼ 0.055, r ¼ À0.245). In conclusion, we observed deregulated expression of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric cancer. We present evidence that either upregulation (for Rac1 and IQGAP1) or downregulation (for Tiam1 and E-cadherin) occurs. Rac1 and E-cadherin expression were not related to prognosis, while trends pointing to favorable prognosis of patients with Tiam1 expression and a lack of IQGAP1 expression were observed. These results indicate that the investigated regulators of E-cadherin-mediated cell adhesion play a role in gastric carcinogenesis.

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Section: The Rac1 Downstream Effector Iqgap1mentioning

confidence: 96%

Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer

et al. 2008

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“…The interaction of ␤-catenin with ␣-catenin appears to be regulated by the small GTPase activating protein IQGAP (reviewed in Kuroda et al, 1999; see also Kuroda et al, 1998;Fukata et al, 1999Fukata et al, , 2001Li et al, 1999). It is interesting to note that the stability of this interaction has also been correlated with tyrosine phosphorylation of ␤-catenin (see below; Ozawa and Kemler, 1998).…”

Section: The Plot Regulatory Interactions At the Cytoplasmic Domain Omentioning

confidence: 99%

Turn‐off, drop‐out: Functional state switching of cadherins

Lilien

Balsamo

Arregui

et al. 2002

Developmental Dynamics

149

116

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The classic cadherins are a group of calcium dependent, homophilic cell-cell adhesion molecules that drive morphogenetic rearrangements and maintain the integrity of cell groups through the formation of adherens junctions. The formation and maintenance of cadherin-mediated adhesions is a multistep process and mechanisms have evolved to regulate each step. This suggests that functional state switching plays an important role in development. Among the many challenges ahead is to determine the developmental role that functional state switching plays in tissue morphogenesis and to define the roles of each of the several regulatory interactions that participate in switching. One correlate of the loss of cadherinmediated adhesion, the "turn-off" of cadherin function, is the exit, or "drop-out" of cells from neural and epithelial layers and their conversion to a motile phenotype. We suggest that epithelial mesenchymal conversions may be initiated by signaling pathways that result in the loss of cadherin function. Tyrosine phosphorylation of ␤-catenin is one such mechanism. Enhanced phosphorylation of tyrosine residues on ␤-catenin is almost invariably associated with loss of the cadherin-actin connection concomitant with loss of adhesive function. There are several tyrosine kinases and phosphatases that have been shown to have the potential to alter the phosphorylation state of ␤-catenin and thus the function of cadherins. Our laboratory has focused on the role of the nonreceptor tyrosine phosphatase PTP1B in regulating the phosphorylation of ␤-catenin on tyrosine residues. Our data suggest that PTP1B is crucial for maintenance of N-cadherin-mediated adhesions in embryonic neural retina cells. By using an L-cell model system constitutively expressing N-cadherin, we have worked out many of the molecular interactions essential for this regulatory interaction. Extracellular cues that bias this critical regulatory interaction toward increased phosphorylation of ␤-catenin may be a critical component of many developmental events.

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“…IQGAP1 is a member of a three-isoform family of proteins that also includes IQGAP2 (Yamashiro et al, 2003) and IQGAP3 . IQGAP1, the most studied, binds calmodulin, cross-links actin filaments, integrates signaling networks (reviewed in Mateer et al, 2003;Brown and Sacks, 2006), and regulates cell-cell contacts (Fukata et al, 1999;Fukata et al, 2001) and the capture of microtubule plus-ends via association with CLIP-170 (Fukata et al, 2002). The current paradigm is that IQGAP1 regulates actin assembly in cooperation with the ARP2/3 complex and the Rho GTPases in different cell types to regulate cell outgrowth and migration (Watanabe et al, 2004;Bensenor et al, 2007;Le Clainche et al, 2007;Wang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

A dual role for IQGAP1 in regulating exocytosis

Rittmeyer

Daniel

Hsu

et al. 2008

Journal of Cell Science

173

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Polarized secretion is a tightly regulated event generated by conserved, asymmetrically localized multiprotein complexes, and the mechanism(s) underlying its temporal and spatial regulation are only beginning to emerge. Although yeast Iqg1p has been identified as a positional marker linking polarity and exocytosis cues, studies on its mammalian counterpart, IQGAP1, have focused on its role in organizing cytoskeletal architecture, for which the underlying mechanism is unclear. Here, we report that IQGAP1 associates and co-localizes with the exocyst-septin complex, and influences the localization of the exocyst and the organization of septin. We further show that activation of CDC42 GTPase abolishes this association and inhibits secretion in pancreatic β-cells. Whereas the N-terminus of IQGAP1 binds the exocyst-septin complex, enhances secretion and abrogates the inhibition caused by CDC42 or the depletion of IQGAP1, the C-terminus, which binds CDC42, inhibits secretion. Pulse-chase experiments indicate that IQGAP1 influences protein-synthesis rates, thus regulating exocytosis. We propose and discuss a model in which IQGAP1 serves as a conformational switch to regulate exocytosis.

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Cdc42 and Rac1 Regulate the Interaction of IQGAP1 with β-Catenin

Cited by 212 publications

References 41 publications

Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer

Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer

Turn‐off, drop‐out: Functional state switching of cadherins

A dual role for IQGAP1 in regulating exocytosis

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