Disease relevance of IQGAP1

• Although overexpression of wild type IQGAP1 promoted neurite outgrowth in N1E-115 neuroblastoma cells, the nonphosphorylatable IQGAP1 S1441A/S1443A had no effect [1].
• Furthermore, we found autoantibodies reacting with IQGAP1 in patients with bullous skin eruptions most apparently belonging to the spectrum of bullous pemphigoid [2].
• RasGAP-like protein IQGAP1 is expressed by human keratinocytes and recognized by autoantibodies in association with bullous skin disease [2].
• Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: its overexpression in carcinomas and association with invasion fronts [3].
• Loss of IQGAP1 also does not affect tumor development or tumor progression, but mutant mice exhibit a significant (P < 0.0001) increase in late-onset gastric hyperplasia relative to wild-type animals of the same genetic background [4].

High impact information on IQGAP1

• Expression of carboxy-terminal fragment of IQGAP1, which includes the CLIP-170 binding region, delocalizes GFP-CLIP-170 from the tips of microtubules and alters the microtubule array [5].
• In Vero fibroblasts, IQGAP1 localizes at the polarized leading edge [5].
• Rho GTPases also capture and stabilise microtubules through their effectors (e.g. IQGAP1, mDia and Par6) near the cell cortex, leading to polarised cell morphology and directional cell migration [6].
• IQGAP1 has roles in many different aspects of cell physiology and interacts with numerous proteins [7].
• silencing of IQGAP1 prevents phagocytic cup formation and inhibits phagocytosis in macrophages [8]
• IQGAP1 is a scaffold protein that integrates signals for localized actin polymerization [9]

Chemical compound and disease context of IQGAP1

• In breast cancer MCF-7 cells, which possess PP2A-C but lack PP2A-A, IQGAP1 was not associated with Rac-beta1 integrin but with PP2A-C, with no distinct F-actin assembly that linked to Rac-beta1 integrin even before treatment with OA [10].
• Melatonin deficiency, increased serotonin level with disturbed melatonin-serotonin interactions and calmodulin antagonism by increased IQGAP1 may be responsible for progression of both types of spinal deformities in neurofibromatosis 1 [11].
• An angiotensin II antagonist, sarcosine-1, threonine-8 angiotensin II ( [Sar1, Thr8] A II), was infused preoperatively in 14 patients with renal artery stenosis [12].
• Infusion of the Ang II antagonist [Sar1, Ile8]Ang II (600 ng/kg/min) for 30 minutes, resulted in a rise in MAP (18.8 +/- 2.1 mm Hg) and more than a twofold increase in plasma ANF level in patients with essential hypertension (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)[13]
• SAR1 is a new IgG2a murine monoclonal antibody derived by immunization with a plant virus expressing the sequence GERDRDR from the C-terminal tail of the gp41 transmembrane glycoprotein of human immunodeficiency virus type 1 (HIV-1) [14].

Biological context of IQGAP1

essential for phagocytosis by recruiting the formin Dia1 [8]

• IQGAP1 regulates the cytoskeleton, promotes cell motility, and modulates E-cadherin-mediated cell-cell adhesion [15].
• In vitro analysis with purified proteins documented that IQGAP1 is a substrate for protein kinase Cepsilon, which catalyzes phosphorylation on Ser-1443 [1].
• Analysis of IQGAP1 constructs with point mutations in single, double, or triple IQ motifs revealed that apocalmodulin bound only to IQ3 and IQ4 [16].
• For IQGAP1, a series of six tandem IQGAP coiled-coil repeats (IRs) located past the C-terminal of the CHD of each subunit support protein dimerization and, by extension, the IRs or an undefined subset of them were thought to be essential for F-actin binding mediated by its CHDs [17].
• While we cannot exclude that functional redundancy with IQGAP2 contributes to the lack of developmental phenotypes, the restricted expression pattern of IQGAP2 is not obviously altered in adult IQGAP1 mutant mice [4].

Anatomical context of IQGAP1

• The interaction with these targets enables IQGAP1 to participate in many cellular functions varying from regulation of the cytoskeleton to gene transcription [18].
• IQGAP1 promotes neurite outgrowth in a phosphorylation-dependent manner [1].
• Here we demonstrate that endogenous IQGAP1 is highly phosphorylated in MCF-7 human breast epithelial cells [1].
• Interactions among IQGAP1, Cdc42, and the cadherin/catenin protein complex regulate Sertoli-germ cell adherens junction dynamics in the testis [19].
• Our results demonstrate IQGAP1, a newly described multifunctional protein, to be constitutively expressed in human keratinocytes where it may contribute to the integrity of the epidermal layer [2].

Associations of IQGAP1 with chemical compounds

• In vitro, the affinity of wild type IQGAP1 for F-actin decreased with increasing concentrations of calmodulin, and this effect was dramatically enhanced by Ca(2+) and required the IQ domains of IQGAP1 [20].
• To elucidate the biological sequelae of phosphorylation, Ser-1441 and Ser-1443 were converted either to alanine, to create a nonphosphorylatable construct, or to glutamic acid and aspartic acid, respectively, to generate a phosphomimetic IQGAP1 [1].
• Mutating the basic charged arginine residues in all four IQ motifs abrogated binding of IQGAP1 to apocalmodulin, but had no effect on its interaction with Ca(2+)/calmodulin [16].
• Here we identify a novel IQGAP1 scaffolding function by isolating the cyclic AMP dependent kinase (PKA) with IQGAP1 [21].
• Zn(2+) binding to S100B is sufficient to promote interaction with IQGAP1 [22].

Physical interactions of IQGAP1

binds Dia1 (mDia1) to [8] localize actin assembly at the leading edge of migrating cells as well as at the phagocytic cup [9]

• IQGAP1 binds ERK2 and modulates its activity [18].
• Here we demonstrate competition between calmodulin and E-cadherin for binding to IQGAP1 both in vitro and in a normal cellular milieu [23].
• Identification of an IQGAP1/AKAP79 complex in beta-cells [21].
• In this issue of Developmental Cell, Watanabe et al. now show a molecular connection between the actin crosslinking protein IQGAP1 and the microtubule-stabilizing protein APC that impacts cells' ability to migrate into a wound [24].
• Phosphorylation of IQGAP1 modulates its binding to Cdc42, revealing a new type of rho-GTPase regulator [25].
• We show that IQGAP1 regulates cell proliferation, which requires phosphorylation of IQGAP1 and binding to CDC42 [26].

Enzymatic interactions of IQGAP1

• Wound assays reveal that IQGAP1 and phosphorylated VEGFR2 accumulate and colocalize at the leading edge in actively migrating ECs [27].

Co-localisations of IQGAP1

• We also provide evidence that, in human astrocytoma cell lines, S100B co-localizes with IQGAP1 at the polarized leading edge and areas of membrane ruffling and that both proteins relocate in a Ca(2+)-dependent manner within newly formed vesicle-like structures [22].
• METHODS AND RESULTS: Confocal microscopy analysis shows that IQGAP1 colocalizes with VE-cadherin at cell-cell contacts in unstimulated human endothelial cells (ECs) [28].

Regulatory relationships of IQGAP1

• Manipulation of intracellular IQGAP1 levels significantly reduced growth factor-stimulated ERK1 and ERK2 activity [18].
• Calmodulin binds to IQGAP1 and regulates its association with Cdc42 and actin [23].
• Recent studies reveal that IQGAP1 regulates cadherin-mediated cell-cell adhesion both positively and negatively [29].
• Overexpression of IQGAP1 in SW480 colon carcinoma cells enhanced beta-catenin-mediated transcriptional co-activation by 1.72-fold, and this stimulation was significantly attenuated upon antagonism of calmodulin using the cell-permeable antagonist CGS9343B [30].
• IQGAP1 regulates reactive oxygen species-dependent endothelial cell migration through interacting with Nox2 [31].

Other interactions of IQGAP1

• The association between ERK2 and IQGAP1 was independent of epidermal growth factor [18].
• Interestingly, IQGAP2 is polarized to the apical membrane of the parietal cells, whereas IQGAP1 is mainly distributed to the basolateral membrane [32].
• In addition, the ability of IQGAP1 to increase the amount of active Cdc42 in cells is abrogated upon removal of this region [15].
• IQGAP1 and calmodulin modulate E-cadherin function [23].
• Furthermore, we demonstrate that constitutively active Cdc42, and to a lesser extent Rac1, enhances the interaction of PTPmu and IQGAP1 [33].
• Our data suggest that IQGAP1 may link the calmodulin and Rap1 signaling pathways [34].

Analytical, diagnostic and therapeutic context of IQGAP1

• Gel filtration analysis suggested that full-length IQGAP1 exists as a combination of monomers, dimers, and larger oligomers [15].
• The protein is selectively recognized by a monoclonal anti-IQGAP1 antibody on western blots and immunoprecipitates from keratinocyte extracts [2].
• Indirect immunofluorescence locates IQGAP1 within individual keratinocytes in a cytoplasmic pattern and along the cell periphery at adhesive sites [2].
• Using Sertoli-germ cell cocultures, it was demonstrated that AJ assembly associated with a transient induction of Cdc42 and IQGAP1, which was not found when Sertoli cells were cultured alone [19].
• IQGAP1 was co-purified with PKA using 5'-cyclic AMP (cAMP) affinity chromatography and PKA activity was co-immunoprecipitated with IQGAP1 using an anti-IQGAP1 antibody [21].

References