Genomes and Genes
ras gtpase activating proteins
Summary: PROTEINS that specifically activate the GTP-phosphohydrolase activity of RAS PROTEINS.
- Jeong H, Li Z, Brown M, Sacks D. IQGAP1 binds Rap1 and modulates its activity. J Biol Chem. 2007;282:20752-62 pubmed..These findings reveal that the interaction of IQGAP1 with Rap1 differs in several respects from its interaction with other small GTPases. Furthermore, our data suggest that IQGAP1 may link the calmodulin and Rap1 signaling pathways. ..
- Mateer S, McDaniel A, Nicolas V, Habermacher G, Lin M, Cromer D, et al. The mechanism for regulation of the F-actin binding activity of IQGAP1 by calcium/calmodulin. J Biol Chem. 2002;277:12324-33 pubmed..Taken together, these results support a model in which a rise in free intracellular Ca(2+) promotes binding of calmodulin to IQGAP1, which in turn inhibits IQGAP1 from binding to cortical actin filaments. ..
- Noritake J, Watanabe T, Sato K, Wang S, Kaibuchi K. IQGAP1: a key regulator of adhesion and migration. J Cell Sci. 2005;118:2085-92 pubmed..Furthermore, Rac1 and Cdc42 link the adenomatous polyposis coli (APC) protein to actin filaments through IQGAP1 at the leading edge and thereby regulate polarization and directional migration. ..
- Liu Q, Walker S, Gao D, Taylor J, Dai Y, Arkell R, et al. CAPRI and RASAL impose different modes of information processing on Ras due to contrasting temporal filtering of Ca2+. J Cell Biol. 2005;170:183-90 pubmed
- Roy M, Li Z, Sacks D. IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. Mol Cell Biol. 2005;25:7940-52 pubmed..Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway. ..
- Leblanc V, Delumeau I, Tocque B. Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells. Oncogene. 1999;18:4884-9 pubmed..These results show that targeting of Ras-GAP could represent a novel anticancer approach. ..
- Vollmer P, Will E, Scheglmann D, Strom M, Gallwitz D. Primary structure and biochemical characterization of yeast GTPase-activating proteins with substrate preference for the transport GTPase Ypt7p. Eur J Biochem. 1999;260:284-90 pubmed..We also report the identification and cloning of a gene from the dimorphic yeast Yarrowia lipolytica that encodes a protein whose primary structure and biochemical activity are significantly related to those of Gyp7p from baker's yeast. ..
- Benseñor L, Kan H, Wang N, Wallrabe H, Davidson L, Cai Y, et al. IQGAP1 regulates cell motility by linking growth factor signaling to actin assembly. J Cell Sci. 2007;120:658-69 pubmed..Based on these observations, we conclude that IQGAP1 links FGF2 signaling to Arp2/3 complex-dependent actin assembly by serving as a binding partner for FGFR1 and as an activator of N-WASP. ..
- Yamaoka Tojo M, Tojo T, Kim H, Hilenski L, Patrushev N, Zhang L, et al. IQGAP1 mediates VE-cadherin-based cell-cell contacts and VEGF signaling at adherence junctions linked to angiogenesis. Arterioscler Thromb Vasc Biol. 2006;26:1991-7 pubmed..To induce angiogenesis, it may function to link VEGFR2 to the VE-cadherin containing adherens junctions, thereby promoting VEGF-stimulated, ROS-dependent tyrosine phosphorylation of VE-cadherin and loss of cell-cell contacts. ..
- Brown M, Bry L, Li Z, Sacks D. IQGAP1 regulates Salmonella invasion through interactions with actin, Rac1, and Cdc42. J Biol Chem. 2007;282:30265-72 pubmed..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. ..
- Cullen P, Lockyer P. Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol. 2002;3:339-48 pubmed..Here, we focus on examining the link between calcium and Ras signalling and, in particular, we speculate as to how the complexity of calcium signalling could regulate Ras activity. ..
- Gigoux V, L Hoste S, Raynaud F, Camonis J, Garbay C. Identification of Aurora kinases as RasGAP Src homology 3 domain-binding proteins. J Biol Chem. 2002;277:23742-6 pubmed..Finally we showed that RasGAP forms a ternary complex with HsAIRK and survivin. This complex may be involved in the regulation of the balance between cell division and apoptosis. ..
- Grohmanova K, Schlaepfer D, Hess D, Gutierrez P, Beck M, Kroschewski R. Phosphorylation of IQGAP1 modulates its binding to Cdc42, revealing a new type of rho-GTPase regulator. J Biol Chem. 2004;279:48495-504 pubmed..We propose that, depending on its phosphorylation state, IQGAP1 might serve as an effector or sequester nucleotide-free Cdc42 to prevent signaling. ..
- Wang Z, Tseng C, Pong R, Chen H, McConnell J, Navone N, et al. The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2. J Biol Chem. 2002;277:12622-31 pubmed..Thus, DOC-2/DAB2 and DIP1/2 appear to represent a unique negative regulatory complex that maintains cell homeostasis. ..
- Le Clainche C, Schlaepfer D, Ferrari A, Klingauf M, Grohmanova K, Veligodskiy A, et al. IQGAP1 stimulates actin assembly through the N-WASP-Arp2/3 pathway. J Biol Chem. 2007;282:426-35 pubmed..We propose that signal-induced relief of the autoinhibited fold of IQGAP1 allows activation of N-WASP to stimulate Arp2/3-dependent actin assembly. ..
- Lockyer P, Wennström S, Kupzig S, Venkateswarlu K, Downward J, Cullen P. Identification of the ras GTPase-activating protein GAP1(m) as a phosphatidylinositol-3,4,5-trisphosphate-binding protein in vivo. Curr Biol. 1999;9:265-8 pubmed..From these results, we conclude that GAP1(m) binds PIP3 in vivo, and it is recruited to the plasma membrane, but does not appear to be activated, following agonist stimulation of PI 3-kinase. ..
- Yang J, Walicki J, Michod D, Dubuis G, Widmann C. Impaired Akt activity down-modulation, caspase-3 activation, and apoptosis in cells expressing a caspase-resistant mutant of RasGAP at position 157. Mol Biol Cell. 2005;16:3511-20 pubmed..Therefore, the role of the second caspase-mediated cleavage of RasGAP is to allow the inactivation of the antiapoptotic function of fragment N so that caspases are no longer hampered in their ability to kill cells. ..
- Bourguignon L, Gilad E, Rothman K, Peyrollier K. Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression. J Biol Chem. 2005;280:11961-72 pubmed
- Brandt D, Marion S, Griffiths G, Watanabe T, Kaibuchi K, Grosse R. Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation. J Cell Biol. 2007;178:193-200 pubmed..Thus, we identify IQGAP1 as a novel component involved in the regulation of phagocytosis by mediating the localization of the actin filament nucleator Dia1. ..
- Yamaoka Tojo M, Ushio Fukai M, Hilenski L, Dikalov S, Chen Y, Tojo T, et al. IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation. Circ Res. 2004;95:276-83 pubmed
- Dong P, Nabeshima K, Nishimura N, Kawakami T, Hachisuga T, Kawarabayashi T, et al. Overexpression and diffuse expression pattern of IQGAP1 at invasion fronts are independent prognostic parameters in ovarian carcinomas. Cancer Lett. 2006;243:120-7 pubmed..Overexpression and diffuse expression pattern of IQGAP1 are potentially useful independent molecular predictors of highly aggressive ovarian carcinomas. ..
- Chen H, Toyooka S, Gazdar A, Hsieh J. Epigenetic regulation of a novel tumor suppressor gene (hDAB2IP) in prostate cancer cell lines. J Biol Chem. 2003;278:3121-30 pubmed..We therefore conclude that epigenetic regulation plays a potential role in regulating hDAB2IP expression in PCa and that these results also provide a new therapeutic strategy for PCa patients. ..
- Brown M, Sacks D. IQGAP1 in cellular signaling: bridging the GAP. Trends Cell Biol. 2006;16:242-9 pubmed..These findings suggest that IQGAP1 integrates signaling pathways and coordinates several fundamental cellular activities. ..
- LaGrassa T, Ungermann C. The vacuolar kinase Yck3 maintains organelle fragmentation by regulating the HOPS tethering complex. J Cell Biol. 2005;168:401-14 pubmed..Because Yck3 also promotes efficient vacuole inheritance, we propose that tethering complex phosphorylation is a part of a general, switch-like mechanism for driving changes in organelle architecture. ..
- Yang J, Michod D, Walicki J, Murphy B, Kasibhatla S, Martin S, et al. Partial cleavage of RasGAP by caspases is required for cell survival in mild stress conditions. Mol Cell Biol. 2004;24:10425-36 pubmed..Executioner caspases therefore control the extent of their own activation by a feedback regulatory mechanism initiated by the partial cleavage of RasGAP that is crucial for cell survival under adverse conditions. ..
- Rittmeyer E, Daniel S, Hsu S, Osman M. A dual role for IQGAP1 in regulating exocytosis. J Cell Sci. 2008;121:391-403 pubmed publisher..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. ..
- Watanabe T, Noritake J, Kaibuchi K. Roles of IQGAP1 in cell polarization and migration. Novartis Found Symp. 2005;269:92-101; discussion 101-5, 223-30 pubmed
- Walker S, Kupzig S, Bouyoucef D, Davies L, Tsuboi T, Bivona T, et al. Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca2+ oscillations. EMBO J. 2004;23:1749-60 pubmed..Thus, RASAL senses the frequency of complex Ca2+ signals, decoding them through a regulation of the activation state of Ras. Our data provide a hitherto unrecognised link between complex Ca2+ signals and the regulation of Ras. ..
- Némorin J, Duplay P. Evidence that Llck-mediated phosphorylation of p56dok and p62dok may play a role in CD2 signaling. J Biol Chem. 2000;275:14590-7 pubmed..We propose that phosphorylation and Src homology 2-mediated association of p56(dok) and p62(dok) with Lck play a selective function in accessory receptor signal transduction mechanisms. ..
- Brandt D, Grosse R. Get to grips: steering local actin dynamics with IQGAPs. EMBO Rep. 2007;8:1019-23 pubmed
- Songyang Z, Yamanashi Y, Liu D, Baltimore D. Domain-dependent function of the rasGAP-binding protein p62Dok in cell signaling. J Biol Chem. 2001;276:2459-65 pubmed..Our results suggest that Dok oligomerization through its multiple domains plays a critical role in Dok signaling in response to tyrosine kinase activation. ..
- Fukata M, Nakagawa M, Itoh N, Kawajiri A, Yamaga M, Kuroda S, et al. Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell-cell dissociation during cell scattering. Mol Cell Biol. 2001;21:2165-83 pubmed
- Briggs M, Sacks D. IQGAP proteins are integral components of cytoskeletal regulation. EMBO Rep. 2003;4:571-4 pubmed..Collectively, these data reveal that IQGAP1 is a fundamental regulator of cytoskeletal function. ..
- Ren J, Li Z, Sacks D. IQGAP1 modulates activation of B-Raf. Proc Natl Acad Sci U S A. 2007;104:10465-9 pubmed..Our data identify a previously unrecognized interaction between IQGAP1 and B-Raf and suggest that IQGAP1 is a scaffold necessary for activation of B-Raf by EGF. ..
- Yang J, Walicki J, Abderrahmani A, Cornu M, Waeber G, Thorens B, et al. Expression of an uncleavable N-terminal RasGAP fragment in insulin-secreting cells increases their resistance toward apoptotic stimuli without affecting their glucose-induced insulin secretion. J Biol Chem. 2005;280:32835-42 pubmed..These data indicate that fragment N protects beta cells without affecting their function. The pathways regulated by fragment N are therefore promising targets for antidiabetogenic therapy. ..
- Tamir I, Stolpa J, Helgason C, Nakamura K, Bruhns P, Daeron M, et al. The RasGAP-binding protein p62dok is a mediator of inhibitory FcgammaRIIB signals in B cells. Immunity. 2000;12:347-58 pubmed..Using chimeric FcgammaRIIB containing the RasGAP-binding domain of p62dok, we demonstrate that p62dok contains all structural information required to mediate the inhibitory effect of FcgammaRIIB on Erk activation. ..
- Watanabe T, Wang S, Noritake J, Sato K, Fukata M, Takefuji M, et al. Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell. 2004;7:871-83 pubmed
- Chen H, Pong R, Wang Z, Hsieh J. Differential regulation of the human gene DAB2IP in normal and malignant prostatic epithelia: cloning and characterization. Genomics. 2002;79:573-81 pubmed..These data indicate that transcriptional regulation of DAB2IP is responsible for the downregulation of DAB2IP expression in prostate cancer cells. ..
- Jadeski L, Mataraza J, Jeong H, Li Z, Sacks D. IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J Biol Chem. 2008;283:1008-17 pubmed..Collectively, our data reveal that IQGAP1 enhances mammary tumorigenesis, suggesting that it may be a target for therapeutic intervention. ..
- Nabeshima K, Shimao Y, Inoue T, Koono M. Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: its overexpression in carcinomas and association with invasion fronts. Cancer Lett. 2002;176:101-9 pubmed..This expression pattern showing stronger signals in deeper portions was most apparent in advanced carcinomas that invaded into the subserosa. These findings supported a role of IQGAP1 in colon carcinoma invasion. ..
- Li Z, Kim S, Higgins J, Brenner M, Sacks D. IQGAP1 and calmodulin modulate E-cadherin function. J Biol Chem. 1999;274:37885-92 pubmed
- Yang J, Widmann C. The RasGAP N-terminal fragment generated by caspase cleavage protects cells in a Ras/PI3K/Akt-dependent manner that does not rely on NFkappa B activation. J Biol Chem. 2002;277:14641-6 pubmed..This indicates that Akt effectors are differentially regulated when fragment N is generated. ..
- Yang J, Widmann C. Antiapoptotic signaling generated by caspase-induced cleavage of RasGAP. Mol Cell Biol. 2001;21:5346-58 pubmed..When caspase activity reaches levels that allow completion of RasGAP cleavage, the resulting RasGAP fragments turn into potent proapoptotic molecules. ..
- Li S, Wang Q, Chakladar A, Bronson R, Bernards A. Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP1. Mol Cell Biol. 2000;20:697-701 pubmed..Thus, IQGAP1 does not serve any essential nonredundant functions during murine development but may serve to maintain the integrity of the gastric mucosa in older animals. ..
- Jiang Y, Ma W, Wan Y, Kozasa T, Hattori S, Huang X. The G protein G alpha12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature. 1998;395:808-13 pubmed..Our results are, to our knowledge, the first to identify direct effectors for G alpha12 and to show that there is a direct link between heterotrimeric and monomeric G proteins. ..
- Osman M, Konopka J, Cerione R. Iqg1p links spatial and secretion landmarks to polarity and cytokinesis. J Cell Biol. 2002;159:601-11 pubmed..Taken together, these findings suggest that Iqg1p recruits landmark proteins to form a targeting patch that coordinates axial budding with cytokinesis. ..
- Mataraza J, Briggs M, Li Z, Entwistle A, Ridley A, Sacks D. IQGAP1 promotes cell motility and invasion. J Biol Chem. 2003;278:41237-45 pubmed..Moreover, invasion mediated by constitutively active Cdc42 was attenuated by IQGAP1DeltaGRD. Thus, IQGAP1 has a fundamental role in cell motility and invasion. ..
- Mataraza J, Li Z, Jeong H, Brown M, Sacks D. Multiple proteins mediate IQGAP1-stimulated cell migration. Cell Signal. 2007;19:1857-65 pubmed..Coupled with the observations that Cdc42 and Rac1 contribute to IQGAP1-stimulated cell migration, these data suggest that IQGAP1 serves as a junction to integrate multiple signalling molecules to facilitate cell migration. ..
- Shannon K, Li R. A myosin light chain mediates the localization of the budding yeast IQGAP-like protein during contractile ring formation. Curr Biol. 2000;10:727-30 pubmed..These results demonstrate that Mlc1p is important for the assembly of the actomyosin ring in budding yeast and that this function is mediated through interaction with Cyk1/Iqg1p. ..
- Faix J, Weber I, Mintert U, Kohler J, Lottspeich F, Marriott G. Recruitment of cortexillin into the cleavage furrow is controlled by Rac1 and IQGAP-related proteins. EMBO J. 2001;20:3705-15 pubmed..This leads to a severe defect in cytokinesis, which is similar to that found in cortexillin I/II double-null mutants. Our observations define a novel and functionally significant signaling pathway that is required for cytokinesis. ..
- Lockyer P, Kupzig S, Cullen P. CAPRI regulates Ca(2+)-dependent inactivation of the Ras-MAPK pathway. Curr Biol. 2001;11:981-6 pubmed..Analysis of the spatio-temporal dynamics of CAPRI indicates that Ca(2+) regulates the GAP by a fast C2 domain-dependent translocation mechanism. ..
- Fukata M, Kaibuchi K. Rho-family GTPases in cadherin-mediated cell-cell adhesion. Nat Rev Mol Cell Biol. 2001;2:887-97 pubmed..Following the identification and characterization of regulators and effectors of Rho GTPases, signal transduction pathways from cadherin to Rho GTPases and, in turn, from Rho GTPases to cadherin, are beginning to be clarified. ..
- Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, et al. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell. 2002;109:873-85 pubmed..These results indicate that Rac1/Cdc42 marks special cortical spots where the IQGAP1 and CLIP-170 complex is targeted, leading to a polarized microtubule array and cell polarization. ..
- Dote H, Toyooka S, Tsukuda K, Yano M, Ouchida M, Doihara H, et al. Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer. Clin Cancer Res. 2004;10:2082-9 pubmed..Our results demonstrate that hDAB2IP methylation frequently is present in breast cancer and plays a key role in hDAB2IP inactivation, suggesting the relationship between hDAB2IP methylation and lymph node metastasis of breast cancer. ..
- Roy M, Li Z, Sacks D. IQGAP1 binds ERK2 and modulates its activity. J Biol Chem. 2004;279:17329-37 pubmed..Our data disclose a previously unidentified communication between IQGAP1 and the ERK pathway and imply that IQGAP1 modulates the Ras/mitogen-activated protein kinase signaling cascade. ..
- Noritake J, Fukata M, Sato K, Nakagawa M, Watanabe T, Izumi N, et al. Positive role of IQGAP1, an effector of Rac1, in actin-meshwork formation at sites of cell-cell contact. Mol Biol Cell. 2004;15:1065-76 pubmed..quot; ..
- Ren J, Li Z, Crimmins D, Sacks D. Self-association of IQGAP1: characterization and functional sequelae. J Biol Chem. 2005;280:34548-57 pubmed..These observations define a sequence of IQGAP1 that is necessary for its oligomerization and demonstrate that self-association is required for the normal cellular function of IQGAP1. ..
- Michod D, Yang J, Chen J, Bonny C, Widmann C. A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells. Oncogene. 2004;23:8971-8 pubmed..Our results demonstrate the feasibility in enhancing the efficacy of currently used drugs to selectively kill cancer cells using peptides derived from pro-apoptotic caspase substrate fragments. ..
- Katata T, Irie K, Fukuhara A, Kawakatsu T, Yamada A, Shimizu K, et al. Involvement of nectin in the localization of IQGAP1 at the cell-cell adhesion sites through the actin cytoskeleton in Madin-Darby canine kidney cells. Oncogene. 2003;22:2097-109 pubmed..These results indicate that nectin is involved in the localization of IQGAP1 at AJs through the actin cytoskeleton. ..
- Shannon K, Li R. The multiple roles of Cyk1p in the assembly and function of the actomyosin ring in budding yeast. Mol Biol Cell. 1999;10:283-96 pubmed..These results demonstrate the critical function of Cyk1p/Iqg1p in regulating various steps of actomyosin ring assembly and cytokinesis. ..
- Lockyer P, Bottomley J, Reynolds J, McNulty T, Venkateswarlu K, Potter B, et al. Distinct subcellular localisations of the putative inositol 1,3,4,5-tetrakisphosphate receptors GAP1IP4BP and GAP1m result from the GAP1IP4BP PH domain directing plasma membrane targeting. Curr Biol. 1997;7:1007-10 pubmed..This difference in localisation has fundamental significance for our understanding of the second messenger functions of IP4. ..
- Leblanc V, Tocque B, Delumeau I. Ras-GAP controls Rho-mediated cytoskeletal reorganization through its SH3 domain. Mol Cell Biol. 1998;18:5567-78 pubmed..These results support the idea that Ras-GAP connects the Ras and Rho pathways and, therefore, regulates the actin cytoskeleton through a mechanism which probably does not involve p190 Rho-GAP. ..