IQGAP1, a Novel Vascular Endothelial Growth Factor Receptor Binding Protein, Is Involved in Reactive Oxygen Species—Dependent Endothelial Migration and Proliferation

Yamaoka‐Tojo, Minako; Ushio‐Fukai, Masuko; Hilenski, Lula; Dikalov, Sergey; Chen, Yuqing E.; Tojo, Taiki; Fukai, Tohru; Fujimoto, Mitsuaki; Patrushev, Nikolay; Wang, Ningning; Kontos, Christopher D.; Bloom, George S.; Alexander, R. Wayne

doi:10.1161/01.res.0000136522.58649.60

Cited by 222 publications

(254 citation statements)

References 36 publications

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“…Future studies will also focus on whether CD47 associates differentially with these processed forms of VEGFR2. Finally, the effects of CD47 ligation on the known associations of VEGFR2 with VE-cadherin, integrins, IQGAP1, and CD36 should be further examined (53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 Inhibits VEGF Receptor-2 Signaling by Disrupting Its Association with CD47

Kaur

Martin‐Manso

Pendrak

et al. 2010

Journal of Biological Chemistry

207

222

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Thrombospondin-1 (TSP1) can inhibit angiogenic responses directly by interacting with VEGF and indirectly by engaging several endothelial cell TSP1 receptors. We now describe a more potent mechanism by which TSP1 inhibits VEGF receptor-2 (VEGFR2) activation through engaging its receptor CD47. CD47 ligation is known to inhibit downstream signaling targets of VEGFR2, including endothelial nitric-oxide synthase and soluble guanylate cyclase, but direct effects on VEGFR2 have not been examined. Based on FRET and co-immunoprecipitation, CD47 constitutively associated with VEGFR2. Ligation of CD47 by TSP1 abolished resonance energy transfer with VEGFR2 and inhibited phosphorylation of VEGFR2 and its downstream target Akt without inhibiting VEGF binding to VEGFR2. The inhibitory activity of TSP1 in large vessel and microvascular endothelial cells was replicated by a recombinant domain of the protein containing its CD47-binding site and by a CD47-binding peptide derived from this domain but not by the CD36-binding domain of TSP1. Inhibition of VEGFR2 phosphorylation was lost when CD47 expression was suppressed in human endothelial cells and in murine CD47-null cells. These results reveal that anti-angiogenic signaling through CD47 is highly redundant and extends beyond inhibition of nitric oxide signaling to global inhibition of VEGFR2 signaling.

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Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 Inhibits VEGF Receptor-2 Signaling by Disrupting Its Association with CD47

Kaur

Martin‐Manso

Pendrak

et al. 2010

Journal of Biological Chemistry

207

222

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“…Salmonella typhimurium has been shown to bind to IQGAP1 which allows S. typhimurium to escape the host immune response allowing for the establishment of chronic infection (Kim et al 2011). Additionally, IQGAP1 was found to be needed to organize ROS-dependent VEGF signaling via VEGFR2 in endothelial cells which may contribute to the repair and maintenance of blood vessels and angiogenesis (Yamaoka-Tojo et al 2004). VEGF signaling is known to induce angiogenesis, increase vascular permeability, and influence inflammation in several ways, all which could increase risk of chronic otitis media by effusion build-up and in- Cheeseman et al 2011).…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

Allen

Chen

Weeks

et al. 2013

JARO

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Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with PG10 −4 and 12 imputed SNPs with PG10 −4 on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P= 1.30×10 −5 ) on chromosome 2 in the independent otitis media population (P=4.7×10 −5 ; meta-analysis P= 1.52×10 −8 ). Three additional SNPs had replication PvaluesG0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P=3.4×10 −7 ) in KIF7 intron 7 (P=0.072), and rs10775247, a nonsynonymous SNP in TICRR exon 2 (P=0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P=0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.

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“…For example, IQGAP1 interacts with the VEGF receptor (VEGFR2) (46), the hyaluronan receptor CD44 (23), the AMPA receptor subunit GluR4 (47), and FGFR1 (fibroblast growth factor receptor 1) (48). However, in contrast to VEGFR2 or FGFR2, where association with IQGAP1 seems to require activation of the receptors, we have shown here the interaction between IQGAP1 and EGFR appears to be ligand-independent.…”

Section: Discussionmentioning

confidence: 99%

MAPK Scaffold IQGAP1 Binds the EGF Receptor and Modulates Its Activation

McNulty

White

et al. 2011

Journal of Biological Chemistry

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Cellular responses produced by EGF are mediated through the receptor (EGFR) and by various enzymes and scaffolds. Recent studies document IQGAP1 as a scaffold for the MAPK cascade, binding directly to B-Raf, MEK, and ERK and regulating their activation in response to EGF. We previously showed that EGF is unable to activate B-Raf in cells lacking IQGAP1. However, the mechanism by which IQGAP1 links B-Raf to EGFR was unknown. Here we report that endogenous EGFR and IQGAP1 co-localize and co-immunoprecipitate in cells. EGF has no effect on the association, but Ca 2؉ attenuates binding. In vitro analysis demonstrated a direct association mediated through the IQ and kinase domains of IQGAP1 and EGFR, respectively. Calmodulin disrupts this interaction. Using a mass spectrometry-based assay, we show that EGF induces phosphorylation of IQGAP1 Ser 1443 , a residue known to be phosphorylated by PKC. This phosphorylation is eliminated by pharmacological inhibition of either EGFR or PKC and transfection with small interfering RNA directed against the PKC␣ isoform. In IQGAP1-null cells, EGF-stimulated tyrosine phosphorylation of EGFR is severely attenuated. Normal levels of autophosphorylation are restored by reconstituting wild type IQGAP1 and enhanced by an IQGAP1 S1443D mutant. Collectively, these data demonstrate a functional interaction between IQGAP1 and EGFR and suggest that IQGAP1 modulates EGFR activation.

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IQGAP1, a Novel Vascular Endothelial Growth Factor Receptor Binding Protein, Is Involved in Reactive Oxygen Species—Dependent Endothelial Migration and Proliferation

Cited by 222 publications

References 36 publications

Thrombospondin-1 Inhibits VEGF Receptor-2 Signaling by Disrupting Its Association with CD47

Thrombospondin-1 Inhibits VEGF Receptor-2 Signaling by Disrupting Its Association with CD47

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

MAPK Scaffold IQGAP1 Binds the EGF Receptor and Modulates Its Activation

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