Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan
* Author for correspondence (e-mail: kaibuchi{at}med.nagoya-u.ac.jp)
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Summary |
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Key words: IQGAP1, Rho-family GTPases, Rac1, Cdc42, Cadherin, CLIP-170, APC, Cell adhesion, Cell polarization
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Introduction |
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IQGAP1 is an effector for Rac and Cdc42 that contains binding sites for actin (Fukata et al., 1997), extracellular signal-regulated kinase 2 (ERK2) (Roy et al., 2004
), calmodulin (Hart et al., 1996
; Joyal et al., 1997
; Ho et al., 1999
), myosin essential light chain (Weissbach et al., 1998
), S100B (Mbele et al., 2002
), Rac/Cdc42 (Hart et al., 1996
; Kuroda et al., 1996
; Swart-Mataraza et al., 2002
; Mataraza et al., 2003a
), ß-catenin (Fukata et al., 1999
; Briggs et al., 2002
), E-cadherin (Kuroda et al., 1998
; Li et al., 1999
), CLIP-170 (Fukata et al., 2002
) and adenomatous polyposis coli (APC) (Watanabe et al., 2004
) (Fig. 1). It appears to play a pivotal role in the control of cell adhesion, polarization and migration. Here, we review recent work that has provided insight into how IQGAP1 functions in these processes.
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Cadherin-mediated cell-cell adhesion |
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More than 80 members of the cadherin superfamily have been identified in the human genome, including classical cadherins (e.g. E-cadherin, VE-cadherin and N-cadherin), Fat-like cadherins, and seven-pass transmembrane cadherins (Tepass et al., 2000; Yagi and Takeichi, 2000
). All cadherins possess extracellular cadherin (EC) domains (also known as cadherin repeats), typically organized as tandem repeats, which mediate their homophilic interactions. Their adhesive activity can be regulated by extracellular Ca2+ and cytoplasmic signaling. Binding of Ca2+ to the linker region between the EC domains allows cadherin molecules to form a rigid and organized structure that is resistant to proteolysis (Steinberg and McNutt, 1999
). Under these conditions, they can form cis dimers and trans dimers. Removal of Ca2+ by EGTA leads to a disordered structure and loss of cadherin-mediated cell-cell adhesion. The cytoplasmic regions of classical cadherins comprise two domains: the C-terminal distal ß-catenin-binding domain (DßD); and the juxtamembrane domain (JMD), which is the p120-catenin-binding site and is thought to regulate clustering, transport and endocytosis of cadherins (Takeichi, 1995
; Adams and Nelson, 1998
; Gumbiner, 2000
; Tepass et al., 2000
).
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Regulation of cadherin-mediated cell-cell adhesion by Rho GTPases |
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Studies using cell-dissociation assays to quantify E-cadherin activity in mouse L fibroblasts stably expressing E-cadherin mutants have examined the basis of these effects. Cells expressing wild-type E-cadherin (EL cells) and cells expressing an E-cadherin mutant in which the cytoplasmic domain has been replaced by the C-terminal domain of -catenin (nE
CL cells) both exhibit E-cadherin-dependent cell-cell adhesion. However, in nE
CL cells, this clearly does not require the DßD of E-cadherin, ß-catenin or the N-terminal region of
-catenin (Nagafuchi et al., 1994
). Significantly, expression of Rac1N17 or Cdc42N17 markedly reduces E-cadherin-dependent adhesion in EL cells but not in nE
CL cells (Fukata et al., 1999
). This observation indicates that Rac1 and Cdc42 regulate E-cadherin activity through the cadherin-catenin complex. By contrast, expression of dominant-negative Rho (RhoN19) slightly reduces E-cadherin activity in both EL cells and nE
CL cells. This suggests that RhoA affects E-cadherin-mediated adhesive activity through another mechanism.
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Regulation of cadherin-mediated cell-cell adhesion by IQGAP1 |
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Recent work, including the use of RNA interference (RNAi), has now examined this issue. We have shown that the inhibition of either IQGAP1 or Rac1 by RNAi reduces the accumulation of actin filaments, E-cadherin and ß-catenin at sites of cell-cell contact in MDCKII cells (Noritake et al., 2004). In addition, we showed that expression of a putative constitutively active mutant of IQGAP1(T1050AX2) (Fig. 1) that cannot bind to Rac1/Cdc42 overcomes the effect of knocking down Rac1 (e.g. promoting actin accumulation). We also found that 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell scattering in cells in which IQGAP1 or Rac1 is knocked down is faster than in control cells (Noritake et al., 2004
). IQGAP1 and Rac1 are thus both necessary for cell-cell adhesion.
Rac1 directly binds to IQGAP1 when the amount of its GTP-bound form increases. This tethers actin filaments, which are also linked to the cadherinß-catenin complex through -catenin. Under these conditions, IQGAP1 does not bind to ß-catenin and cannot dissociate
-catenin from the cadherin-catenin complex, and the ratio of E-cadherinß-catenin
-catenin complex to E-cadherinß-cateninIQGAP1 complex is high. This state confers strong adhesive activity (Fig. 2). Since IQGAP1 has anti-GTPase activity (Hart et al., 1996
), it might sustain the amount of GTP-bound Rac1 at sites of cell-cell contact, leading to stable adhesion. Izumi et al. recently reported that the inhibition of endocytosis of trans-interacting E-cadherin is mediated by reorganization of the actin cytoskeleton by the IQGAP1-Rac/Cdc42 complex (Izumi et al., 2004
). Thus, IQGAP1 behaves as a positive regulator downstream of Rac1.
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By contrast, IQGAP1 is freed from Rac1 and Cdc42, and interacts with ß-catenin to dissociate -catenin from the cadherin-catenin complex when the amounts of inactivated Rac1 and Cdc42 increase during the action of certain extracellular signals such as HGF or TPA (see below). In this case, the ratio of E-cadherinß-cateninIQGAP1 complex to E-cadherinß-catenin
-catenin complex is high, resulting in weak adhesion and cell-cell dissociation (Fig. 2). Thus, IQGAP1 negatively regulates E-cadherin-mediated cell-cell adhesion.
The physiological processes in which this Rac1/Cdc42/IQGAP1 system is involved are unclear. It functions in cell-cell dissociation during HGF- or TPA-induced cell scattering, which is thought to be a model for the epithelial-mesenchymal transition (EMT) and dispersal of cancer cells. Time-lapse analyses using green fluorescent protein (GFP)-tagged -catenin showed that
-catenin disappears from cell-cell contacts before the cells dissociate during cell scattering. Rac1V12, Cdc42V12 and a dominant-negative mutant of IQGAP1 (a C-terminal fragment; see Fig. 1) that interacts with endogenous IQGAP1 and delocalizes it from sites of cell-cell contact inhibit the disappearance of
-catenin. Furthermore, on stimulation with HGF or TPA, the level of GTP-bound Rac1 and the proportion of Rac1 complexed with IQGAP1 decrease, and the proportion of IQGAP1 complexed with ß-catenin increases (Fukata et al., 2001
).
-catenin-deficient mouse teratocarcinoma F9 cells display a scattered phenotype under conditions in which parental or
-catenin-reexpressing cells form compact colonies (Li et al., 2000
). This indicates that loss of
-catenin results in loss of cell-cell adhesion and a scattered phenotype. Since IQGAP1 dissociates
-catenin from the cadherin-catenin complex and dominant-negative IQGAP1 inhibits the disappearance of
-catenin from sites of cell-cell contact during cell scattering, these results indicate that the Rac1/Cdc42/IQGAP1 system is involved in cell-cell dissociation induced by HGF or TPA. Given that this represents a model for epithelial reorganization and the EMT, IQGAP1 might have a more general role in these processes. Indeed, the phenotypes of IQGAP1-knockout mice and its upregulation in certain cancer support this idea (see Perspectives section).
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Cell polarization and Rho family GTPases |
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Time-lapse imaging has begun to reveal when and where signaling molecules, cytoskeletal components, cell adhesion molecules and vesicles are asymmetrically distributed during cell polarization. The molecular mechanisms involved and how the overall series of events are integrated remain mysterious. However, it is clear that Rho-family GTPases play an important role through regulation of the cytoskeleton and assembly of matrix adhesion complexes (Hall, 1998; Fukata et al., 2003
; Nelson, 2003
; Ridley et al., 2003
; Raftopoulou and Hall, 2004
) in various cell types, including T cells (Stowers et al., 1995
), fibroblasts (Nobes and Hall, 1999
), macrophages (Allen et al., 1998
), astrocytes (Etienne-Manneville and Hall, 2001
; Etienne-Manneville and Hall, 2003
), epithelial cells (Kroschewski et al., 1999
) and neuronal cells (Luo, 2000
; Schwamborn and Püschel, 2004
). Rac1 and Cdc42 participate in polarization of T cells towards antigen-presenting cells, in the directed movement of fibroblasts, macrophages and astrocytes, and in the apico-basolateral polarization of epithelial cells (Etienne-Manneville and Hall, 2002
). Cdc42 is also known to participate in cell polarization in Caenorhabditis elegans embryos by interacting with the PAR-3PAR-6PKC-3 complex (Gotta et al., 2001
; Kay and Hunter, 2001
). Recently, the regulatory mechanisms by which Rac1 and Cdc42 control the actin cytoskeleton have been revealed through the identification and characterization of effectors such as N-WASP, PAK and IQGAP1 (Kaibuchi et al., 1999
; Raftopoulou and Hall, 2004
). Rho-family GTPases also seem to regulate microtubule organization and dynamics (Fukata et al., 2003
; Gundersen et al., 2004
). Again IQGAP1 is implicated, and intensive analyses are beginning to clarify how Rho-family GTPases use this protein to regulate cell polarity through reorganization of the actin cytoskeleton and microtubules.
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Cell polarization by IQGAP1 and CLIP-170 |
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CLIP-170 interacts with IQGAP1 (Fukata et al., 2002), which can associate with microtubules through CLIP-170 in vitro. In fibroblasts, IQGAP1 colocalizes with actin filaments at the polarized leading edge, to which CLIP-170 and microtubules are targeted. Activated Rac1/Cdc42 forms a tripartite complex with IQGAP1 and CLIP-170, enhances the interaction of IQGAP1 with CLIP-170, and captures GFPCLIP-170 at the leading edge and the base of filopodia. Expression of the constitutively active mutant IQGAP1(T1050AX2) bypasses the stimulatory effect of Rac1/Cdc42 on the IQGAP1CLIP-170 interaction and induces formation of multiple leading edges (Fukata et al., 2002
). We therefore propose that Rac1/Cdc42 marks cortical spots to which the IQGAP1CLIP-170 complex is targeted, leading to formation of polarized microtubule arrays and cell polarization. Knocking down IQGAP1 by RNAi decreases the number of immobilized GFPCLIP-170 complexes at the cell periphery facing a wound, which indicates that stabilization of the plus-ends of microtubules at these sites requires IQGAP1 (Watanabe et al., 2004
).
Microtubules frequently follow similar tracks during polymerization. They might therefore be guided along common cytoskeletal elements to specific sites in cells. How is this accomplished during polarization? The most likely candidates for such tracks are actin filaments (Fig. 3). The actin-based motor myosin VI interacts with CLIP-190 (Lantz and Miller, 1998), the Drosophila homolog of CLIP-170, and some actin-binding proteins can interact with +Tips, such as IQGAP1. ACF7, a member of the spectraplakin family of cytoskeletal crosslinking proteins, interacts with both actin and microtubules, and seems to play a key role. In ACF7-null endodermal cells, EB1 and CLIP-170 localize to the tips of microtubules, but microtubules do not grow along actin filaments (Kodama et al., 2003
). Furthermore, in the absence of ACF7, the microtubules do not pause and become tethered to actin-rich cortical sites. Instead, they are less-stable, longer structures that have skewed cytoplasmic trajectories (Kodama et al., 2003
).
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Migration mechanisms involving IQGAP1 and APC |
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In directionally migrating cells, IQGAP1 accumulates at the leading edge (Hart et al., 1996; Kuroda et al., 1996
; Mataraza et al., 2003b
) and crosslinks actin filaments (Briggs and Sacks, 2003
). Furthermore knocking down IQGAP1 by RNAi or transfection of a dominant-negative IQGAP1 mutant markedly reduces cell motility (Mataraza et al., 2003b
). More recent experiments have shown that IQGAP1 directly interacts with APC and that they both colocalize at the leading edge with Rac1 and Cdc42. Activated Rac1 and Cdc42 form a tripartite complex with IQGAP1 and APC (Watanabe et al., 2004
). The depletion of IQGAP1 or APC by RNAi inhibits formation of an actin meshwork at the leading edge, as well as cell migration, immobilization of the plus-ends of microtubules and polarization of the MTOC. This often induces formation of protrusions in the direction of movement instead of a typical leading edge. These atypical structures might be caused by lack of an actin meshwork in the space beneath the leading edge, which longer microtubules have invaded (Bradke and Dotti, 1999
). Constitutively active IQGAP1, which can induce formation of multiple leading edges (Fukata et al., 2002
), provides anomalous accumulation sites for APC; this depends on actin filaments and inhibits proper cell migration. Thus, IQGAP1 appears to anchor APC to actin filaments at specific cortical sites.
On the basis of the study discussed above, we can propose the following model for migration (Fig. 4). Rac1 and Cdc42 are activated by extracellular signals through receptors and GEFs at the leading edge. We have recently shown that the PAR-6PAR-3 complex mediates the Cdc42-induced Rac1 activator through the direct interaction with Rac-specific GEFs, STEF and Tiam1 (Nishimura et al., 2005). Rac1 and Cdc42 then induce the polymerization of actin filaments through various effectors. They also mark spots where IQGAP1 tethers actin filaments. IQGAP1 links APC to actin filaments and captures the plus-ends of microtubules through CLIP-170. Then APC directly and/or indirectly stabilizes microtubules, which is necessary for generation of a stable actin meshwork at the leading edge. APC binds to APC-stimulated GEF (Asef), activating its Rac1 GEF activity (Kawasaki et al., 2000
), and Rac1 activated in this way may affect not only microtubules but also actin filaments, through other effectors. This would provide a local positive-feedback loop that sustains cell migration.
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Perspectives |
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IQGAP1 thus seems to be involved in several human diseases, and it is conceivable that the dysregulation of cadherin-mediated cell-cell adhesion and the misregulation of cell polarization by IQGAP1 and Rho GTPases promote tumor metastasis and intractable inflammatory diseases that often lead to death. If so, modulation of the signaling pathways linking IQGAP1 and cadherins or cell polarization might provide the basis for therapies for these diseases.
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References |
---|
Adams, C. L. and Nelson, W. J. (1998). Cytomechanics of cadherin-mediated cell-cell adhesion. Curr. Opin. Cell Biol. 10, 572-577.[CrossRef][Medline]
Allen, W. E., Zicha, D., Ridley, A. J. and Jones, G. E. (1998). A role for Cdc42 in macrophage chemotaxis. J. Cell Biol. 141, 1147-1157.
Barth, A. I., Siemers, K. A. and Nelson, W. J. (2002). Dissecting interactions between EB1, microtubules and APC in cortical clusters at the plasma membrane. J. Cell Sci. 115, 1583-1590.
Bradke, F. and Dotti, C. G. (1999). The role of local actin instability in axon formation. Science 283, 1931-1934.
Braga, V., Machesky, L. M., Hall, A. and Hotchin, N. A. (1997). The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J. Cell Biol. 137, 1421-1431.
Briggs, M. W. and Sacks, D. B. (2003). IQGAP proteins are integral components of cytoskeletal regulation. EMBO Rep. 4, 571-574.
Briggs, M. W., Li, Z. and Sacks, D. B. (2002). IQGAP1-mediated stimulation of transcriptional co-activation by beta-catenin is modulated by calmodulin. J. Biol. Chem. 277, 7453-7465.
Brill, S., Li, S., Lyman, C. W., Church, D. M., Wasmuth, J. J., Weissbach, L., Bernards, A. and Snijders, A. J. (1996). The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases. Mol. Cell. Biol. 16, 4869-4878.[Abstract]
Etienne-Manneville, S. and Hall, A. (2001). Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell 106, 489-498.[CrossRef][Medline]
Etienne-Manneville, S. and Hall, A. (2002). Rho GTPases in cell biology. Nature 420, 629-635.[CrossRef][Medline]
Etienne-Manneville, S. and Hall, A. (2003). Cdc42 regulates GSK-3 and adenomatous polyposis coli to control cell polarity. Nature 421, 753-756.[CrossRef][Medline]
Fukata, M., Kuroda, S., Fujii, K., Nakamura, T., Shoji, I., Matsuura, Y., Okawa, K., Iwamatsu, A., Kikuchi, A. and Kaibuchi, K. (1997). Regulation of cross-linking of actin filament by IQGAP1, a target for Cdc42. J. Biol. Chem. 272, 29579-29583.
Fukata, M., Kuroda, S., Nakagawa, M., Kawajiri, A., Itoh, N., Shoji, I., Matsuura, Y., Yonehara, S., Fujisawa, H., Kikuchi, A. et al. (1999). Cdc42 and Rac1 regulate the interaction of IQGAP1 with ß-catenin. J. Biol. Chem. 274, 26044-26050.
Fukata, M., Nakagawa, M., Itoh, N., Kawajiri, A., Yamaga, M., Kuroda, S. and Kaibuchi, K. (2001). Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell-cell dissociation during cell scattering. Mol. Cell. Biol. 21, 2165-2183.
Fukata, M., Watanabe, T., Noritake, J., Nakagawa, M., Yamaga, M., Kuroda, S., Matsuura, Y., Iwamatsu, A., Perez, F. and Kaibuchi, K. (2002). Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 109, 873-885.[CrossRef][Medline]
Fukata, M., Nakagawa, M. and Kaibuchi, K. (2003). Roles of Rho-family GTPases in cell polarisation and directional migration. Curr. Opin. Cell Biol. 15, 590-597.[CrossRef][Medline]
Goode, B. L., Drubin, D. G. and Barnes, G. (2000). Functional cooperation between the microtubule and actin cytoskeletons. Curr. Opin. Cell Biol. 12, 63-71.[CrossRef][Medline]
Gotta, M., Abraham, M. C. and Ahringer, J. (2001). CDC-42 controls early cell polarity and spindle orientation in C. elegans. Curr. Biol. 11, 482-488.[CrossRef][Medline]
Gulli, M. P. and Peter, M. (2001). Temporal and spatial regulation of Rho-type guanine-nucleotide exchange factors: the yeast perspective. Genes Dev. 15, 365-379.
Gumbiner, B. M. (2000). Regulation of cadherin adhesive activity. J. Cell Biol. 148, 399-404.
Gundersen, G. G. (2002). Evolutionary conservation of microtubule-capture mechanisms. Nat. Rev. Mol. Cell. Biol. 3, 296-304.[CrossRef][Medline]
Gundersen, G. G., Gomes, E. R. and Wen, Y. (2004). Cortical control of microtubule stability and polarization. Curr. Opin. Cell Biol. 16, 106-112.[CrossRef][Medline]
Hall, A. (1998). Rho GTPases and the actin cytoskeleton. Science 279, 509-514.
Hart, M. J., Callow, M. G., Souza, B. and Polakis, P. (1996). IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J. 15, 2997-3005.[Abstract]
Ho, Y. D., Joyal, J. L., Li, Z. and Sacks, D. B. (1999). IQGAP1 integrates Ca2+/calmodulin and CDC42 signaling. J. Biol. Chem. 274, 464-470.
Hordijk, P. L., ten Klooster, J. P., van der Kammen, R. A., Michiels, F., Oomen, L. C., Collard, J. G. (1997). Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science 278, 1464-1466.
Izumi, G., Sakisaka, T., Baba, T., Tanaka, S., Morimoto, K. and Takai, Y. (2004). Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. J. Cell Biol. 166, 237-248.
Joyal, J. L., Annan, R. S., Ho, Y. D., Huddleston, M. E., Carr, S. A., Hart, M. J. and Sacks, D. B. (1997). Calmodulin modulates the interaction between IQGAP1 and Cdc42. Identification of IQGAP1 by nanoelectrospray tandem mass spectrometry. J. Biol. Chem. 272, 15419-15425.
Kaibuchi, K., Kuroda, S. and Amano, M. (1999). Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu. Rev. Biochem. 68, 459-486.[CrossRef][Medline]
Kawasaki, Y., Senda, T., Ishidate, T., Koyama, R., Morishita, T., Iwayama, Y., Higuchi, O. and Akiyama, T. (2000). Asef, a link between the tumor suppressor APC and G-protein signaling. Science 289, 1194-1197.
Kay, A. J. and Hunter, C. P. (2001). CDC-42 regulates PAR protein localization and function to control cellular and embryonic polarity in C. elegans. Curr. Biol. 11, 474-481.[CrossRef][Medline]
Kodama, A., Takaishi, K., Nakano, K., Nishioka, H. and Takai, Y. (1999). Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells. Oncogene 18, 3996-4006.[CrossRef][Medline]
Kodama, A., Karakesisoglou, I., Wong, E., Vaezi, A. and Fuchs, E. (2003). ACF7: an essential integrator of microtubule dynamics. Cell 115, 343-354.[CrossRef][Medline]
Kroschewski, R., Hall, A. and Mellman, I. (1999). Cdc42 controls secretory and endocytic transport to the basolateral plasma membrane of MDCK cells. Nat. Cell Biol. 1, 8-13.[CrossRef][Medline]
Kuroda, S., Fukata, M., Kobayashi, K., Nakafuku, M., Nomura, N., Iwamatsu, A. and Kaibuchi, K. (1996). Identification of IQGAP as a putative target for the small GTPases, CDC42 and Rac1. J. Biol. Chem. 271, 23363-23367.
Kuroda, S., Fukata, M., Fujii, K., Nakamura, T., Izawa, I. and Kaibuchi, K. (1997). Regulation of cell-cell adhesion of MDCK cells by Cdc42 and Rac1 small GTPases. Biochem. Biophys. Res. Commun. 240, 430-435.[CrossRef][Medline]
Kuroda, S., Fukata, M., Nakagawa, M., Fujii, K., Nakamura, T., Ookubo, T., Izawa, I., Nagase, T., Nomura, N., Tani, H. et al. (1998). Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin-mediated cell-cell adhesion. Science 281, 832-835.
Lantz, V. A. and Miller, K. G. (1998). A class VI unconventional myosin is associated with a homologue of a microtubule-binding protein, cytoplasmic linker protein-170, in neurons and at the posterior pole of Drosophila embryos. J. Cell Biol. 140, 897-910.
Li, S., Wang, Q., Chakladar, A., Bronson, R. T. and Bernards, A. (2000). Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP1. Mol. Cell. Biol. 20, 697-701.
Li, Z., Kim, S. H., Higgins, J. M., Brenner, M. B. and Sacks, D. B. (1999). IQGAP1 and calmodulin modulate E-cadherin function. J. Biol. Chem. 274, 37885-37892.
Luo, L. (2000). Rho GTPases in neuronal morphogenesis. Nat. Rev. Neurosci. 1, 173-180.[CrossRef][Medline]
Mackay, D. J. and Hall, A. (1998). Rho GTPases. J. Biol Chem. 273, 20685-20688.
Mataraza, J. M., Briggs, M. W., Li, Z., Frank, R. and Sacks, D. B. (2003a). Identification and characterization of the Cdc42-binding site of IQGAP1. Biochem. Biophys. Res. Commun. 305, 315-321.[CrossRef][Medline]
Mataraza, J. M., Briggs, M. W., Li, Z., Entwistle, A., Ridley, A. J. and Sacks, D. B. (2003b). IQGAP1 promotes cell motility and invasion. J. Biol. Chem. 278, 41237-41245.
Matsumoto, Y., Oshida, T., Obayashi, I., Imai, Y., Matsui, K., Yoshida, N. L., Nagata, N., Ogawa, K., Obayashi, M., Kashiwabara, T. et al. (2002). Identification of highly expressed genes in peripheral blood T cells from patients with atopic dermatitis. Int. Arch. Allergy Immunol. 129, 327-340.[CrossRef][Medline]
Mbele, G. O., Deloulme, J. C., Gentil, B. J., Delphin, C., Ferro, M., Garin, J., Takahashi, M. and Baudier, J. (2002). The zinc- and calcium-binding S100B interacts and co-localizes with IQGAP1 during dynamic rearrangement of cell membranes. J. Biol. Chem. 277, 49998-50007.
Mimori-Kiyosue, Y., Shiina, N. and Tsukita, S. (2000a). The dynamic behavior of the APC-binding protein EB1 on the distal ends of microtubules. Curr. Biol. 10, 865-868.[CrossRef][Medline]
Mimori-Kiyosue, Y., Shiina, N. and Tsukita, S. (2000b). Adenomatous polyposis coli (APC) protein moves along microtubules and concentrates at their growing ends in epithelial cells. J. Cell Biol. 148, 505-518.
Nagafuchi, A., Ishihara, S. and Tsukita, S. (1994). The roles of catenins in the cadherin-mediated cell adhesion: functional analysis of E-cadherin--catenin fusion molecules. J. Cell Biol. 127, 235-245.[Abstract]
Näthke, I. (2004). APC at a glance. J. Cell Sci. 117, 4873-4875.
Nelson, W. J. (2003). Adaptation of core mechanisms to generate cell polarity. Nature 422, 766-774.[CrossRef][Medline]
Nishimura, T., Yamaguchi, T., Kato, K., Yoshizawa, M., Nabeshima, Y. I., Ohno, S., Hoshino, M., Kaibuchi, K. (2005). PAR-6PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat. Cell Biol. 7, 270-277.[CrossRef][Medline]
Nobes, C. D. and Hall, A. (1999). Rho GTPases control polarity, protrusion, and adhesion during cell movement. J. Cell Biol. 144, 1235-1244.
Noritake, J., Fukata, M., Sato, K., Nakagawa, M., Watanabe, T., Izumi, N., Wang, S., Fukata, Y. and Kaibuchi, K. (2004). Positive role of IQGAP1, an effector of Rac1, in actin-meshwork formation at sites of cell-cell contact. Mol. Biol. Cell 15, 1065-1076.
Palazzo, A. F., Joseph, H. L., Chen, Y., Dujardin, D. L., Alberts, A. S., Pfister, K. K., Vallee, R. B. and Gundersen, G. G. (2001). Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Curr. Biol. 11, 1536-1541.[CrossRef][Medline]
Perez, F., Diamantopoulos, G. S., Stalder, R. and Kreis, T. E. (1999). CLIP-170 highlights growing microtubule ends in vivo. Cell 96, 517-527.[CrossRef][Medline]
Pierre, P., Scheel, J., Rickard, J. E., Kreis, T. E. (1992). CLIP-170 links endocytic vesicles to microtubules. Cell 70, 887-900.[CrossRef][Medline]
Presslauer, S., Hinterhuber, G., Cauza, K., Horvat, R., Rappersberger, K., Wolff, K. and Foedinger, D. (2003). RasGAP-like protein IQGAP1 is expressed by human keratinocytes and recognized by autoantibodies in association with bullous skin disease. J. Invest. Dermatol. 120, 365-371.[CrossRef][Medline]
Raftopoulou, M. and Hall, A. (2004). Cell migration: Rho GTPases lead the way. Dev. Biol. 265, 23-32.[CrossRef][Medline]
Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., Parsons, J. T. and Horwitz, A. R. (2003). Cell migration: integrating signals from front to back. Science 302, 1704-1709.
Roy, M., Li, Z. and Sacks, D. B. (2004). IQGAP1 binds ERK2 and modulates its activity. J. Biol. Chem. 279, 17329-17337.
Schuyler. S. C. and Pellman, D. (2001). Microtubule `plus-end-tracking proteins': the end is just the beginning. Cell 105, 421-424.[CrossRef][Medline]
Schwamborn, J. C. and Püschel, A. W. (2004). The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat. Neurosci. 7, 923-929.[CrossRef][Medline]
Schwartz, M. (2004). Rho signalling at a glance. J. Cell Sci. 117, 5457-5458.
Steinberg, M. S. and McNutt, P. M. (1999). Cadherins and their connections: adhesion junctions have broader functions. Curr. Opin. Cell Biol. 11, 554-560.[CrossRef][Medline]
Stowers, L., Yelon, D., Berg, L. J. and Chant, J. (1995). Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Proc. Natl. Acad. Sci. USA 92, 5027-5031.
Sugimoto, N., Imoto, I., Fukuda, Y., Kurihara, N., Kuroda, S., Tanigami, A., Kaibuchi, K., Kamiyama, R. and Inazawa, J. (2001). IQGAP1, a negative regulator of cell-cell adhesion, is upregulated by gene amplification at 15q26 in gastric cancer cell lines HSC39 and 40A. J. Hum. Genet. 46, 21-25.[CrossRef][Medline]
Swart-Mataraza, J. M., Li, Z. and Sacks, D. B. (2002). IQGAP1 is a component of CDC42 signaling to the cytoskeleton. J. Biol. Chem. 277, 24753-24763.
Takaishi, K., Sasaki, T., Kotani, H., Nishioka, H. and Takai, Y. (1997). Regulation of cell-cell adhesion by Rac and Rho small G proteins in MDCK cells. J. Cell Biol. 139, 1047-1059.
Takeichi, M. (1995). Morphogenetic roles of classic cadherins. Curr. Opin. Cell Biol. 7, 619-627.[CrossRef][Medline]
Takemoto, H., Doki, Y., Shiozaki, H., Imamura, H., Utsunomiya, T., Miyata, H., Yano, M., Inoue, M., Fujiwara, Y. and Monden, M. (2001). Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by E-cadherin in gastric cancers. Int. J. Cancer 91, 783-788.[CrossRef][Medline]
Tepass, U., Truong, K., Godt, D., Ikura, M. and Peifer, M. (2000). Cadherins in embryonic and neural morphogenesis. Nat. Rev. Mol. Cell. Biol. 1, 91-100.[CrossRef][Medline]
Tsukita, S., Tsukita, S., Nagafuchi, A. and Yonemura, S. (1992). Molecular linkage between cadherins and actin filaments in cell-cell adherens junctions. Curr. Opin. Cell Biol. 4, 834-839.[CrossRef][Medline]
Van Aelst, L. and D'Souza-Schorey, C. (1997). Rho GTPases and signaling networks. Genes Dev. 11, 2295-2322.
Vaughan, K. T., Tynan, S. H., Faulkner, N. E., Echeverri, C. J. and Vallee, R. B. (1999). Colocalization of cytoplasmic dynein with dynactin and CLIP-170 at microtubule distal ends. J. Cell Sci. 112, 1437-1447.
Watanabe, T., Wang, S., Noritake, J., Sato, K., Fukata, M., Takefuji, M., Nakagawa, M., Izumi, N., Akiyama, T. and Kaibuchi, K. (2004). Interaction with IQGAP1 links APC to Rac1, Cdc42 and actin filaments during cell polarization and migration. Dev. Cell. 7, 871-883.[CrossRef][Medline]
Weissbach, L., Bernards, A. and Herion, D. W. (1998). Binding of myosin essential light chain to the cytoskeleton-associated protein IQGAP1. Biochem. Biophys. Res. Commun. 251, 269-276.[CrossRef][Medline]
Yagi, T. and Takeichi, M. (2000). Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev. 14, 1169-1180.
Yamaoka-Tojo, M., Ushio-Fukai, M., Hilenski, L., Dikalov, S. I., Chen, Y. E., Tojo, T., Fukai, T., Fujimoto, M., Patrushev, N. A., Wang, N. et al. (2004). IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species-dependent endothelial migration and proliferation. Circ. Res. 95, 276-283.