Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells

Miao, Robert Q.; Gao, Yuan; Harrison, Kathryn; Prendergast, Jay; Acevedo, Lisette M.; Yu, Jun; Hu, Fenghua; Strittmatter, Stephen M.; Sessa, William C.

doi:10.1073/pnas.0602427103

Cited by 132 publications

(204 citation statements)

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“…To detect AP-KS binding, transfected HEK-293 cells were washed with Hanks' balanced salt solution and then incubated with AP-KS fusion protein in Dulbecco's modified Eagle's medium containing 20 mM HEPES and 1 mg/ml bovine serum albumin for 2 h at 4°C. The bound AP-KS was detected using the blue substrate kit (15). The blue staining was examined by microscopy.…”

Section: Methodsmentioning

confidence: 99%

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Shen

Smith

Hsu

et al. 2009

Journal of Biological Chemistry

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Kallistatin is a plasma protein that exhibits pleiotropic effects in vasodilation, anti-angiogenesis, and anti-inflammation. To isolate a kallistatin-binding protein that mediates the vascular actions of kallistatin, we screened and identified a positive clone from a human heart cDNA expression library by using an alkaline phosphatase-kallistatin fusion protein binding assay. Sequence analysis revealed that kallistatin-binding protein is human Kruppel-like factor 4 (KLF4). KLF4 was localized on the plasma membrane of HEK-293 cells and endothelial cells overexpressing KLF4. KLF4 and kallistatin complex formation was identified in endothelial cells by immunoprecipitation followed by immunoblotting. We showed that kallistatin inhibits tumor necrosis factor-␣-induced NF-B activation, as well as vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression in endothelial cells, whereas knockdown of KLF4 by small interfering RNA oligonucleotide abolished the effect of kallistatin. Kallistatin increased endothelial nitric-oxide synthase (eNOS) expression and nitric oxide levels, and these effects were also blocked by KLF4 small interfering RNA oligonucleotide. Moreover, inhibition of eNOS by RNA interference or by NOS inhibitor abolished the blocking effect of kallistatin on vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression. In summary, we identified KLF4 as a kallistatin-binding protein, which has a novel role in mediating the anti-inflammatory actions of kallistatin via increasing eNOS expression in endothelial cells. This study provides a new target for modulating endothelial function in vascular disease.Kallistatin was discovered as a tissue kallikrein inhibitor from human plasma (1, 2). Recent studies indicate that kallistatin exerts pleiotropic effects such as vasodilation and inhibition of angiogenesis, tumor growth, inflammation, and oxidative stress, independent of tissue kallikrein (3-7). We showed that an intravenous bolus injection of human kallistatin caused a rapid and transient reduction of mean arterial blood pressure in anesthetized rats and that kallistatin induced relaxation in isolated aorta rings (3). Moreover, a high affinity binding site for kallistatin was identified in the aortic membrane using 125 Ilabeled kallistatin (3). Furthermore, kallistatin directly stimulated the proliferation and migration of cultured vascular smooth muscle cells by activating mitogen-activated protein kinases (8). These findings suggest the presence of kallistatin receptors or binding proteins that mediate its effects in the vasculature. However, the identity of the kallistatin receptor/ binding protein has not been determined.Kallistatin is a negative acute-phase protein, which is reduced after acute lipopolysaccharide-induced inflammation and in chronic inflammatory disease (9). Transgenic mice overexpressing kallistatin are more resistant to lipopolysaccharideinduced lethality (10). Kallistatin administration via gene delivery significantly decreased neutroph...

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Section: Methodsmentioning

confidence: 99%

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Shen

Smith

Hsu

et al. 2009

Journal of Biological Chemistry

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“…Recently, NgBR and its homologs in mice and yeast (NUS1) were identified as necessary subunits for CPT activities in respective organisms (35). NgBR also interacts with Nogo-B and NPC2 for entirely unrelated physiological events, such as remodeling vascular epithelial cells and controlling intracellular trafficking of cholesterol, respectively (23,25). Therefore, NgBR operates as an ER-residing, multifaceted scaffolding protein in humans.…”

Section: Cptl2 Is Necessary But Not Sufficient For Nr Biosynthesis Inmentioning

confidence: 99%

“…It was recently identified that the human Nogo-B receptor (NgBR) shares weak sequence homology to CPT (Ͻ15% at the amino acid level), and it lacks all five motifs conserved in all CPTs (23,24). In humans, NgBR interacts with the Nogo-B peptide and Niemann-Pick type C2 (NPC2) protein to mediate signals for the proliferation of epithelial cells and to regulate intracellular cholesterol trafficking, respectively (23,25).…”

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confidence: 99%

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A Lettuce (Lactuca sativa) Homolog of Human Nogo-B Receptor Interacts with cis-Prenyltransferase and Is Necessary for Natural Rubber Biosynthesis

Chakrabarty

Tran

et al. 2015

Journal of Biological Chemistry

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Background: Natural rubber biosynthesis in lettuce (Lactuca sativa) and other plants remains elusive. Results: An unusual cis-prenyltransferase-like protein interacts with and tethers a cis-prenyltransferase on endoplasmic reticulum, and its RNAi-silencing eliminates natural rubber. Conclusion: cis-Prenyltransferase-like protein is a necessary component in natural rubber biosynthesis in lettuce. Significance: The results presented here suggest hetero-protein complexes are involved in natural rubber biosynthesis.

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“…For example, a 2006 study showed that NOGO plays a role in forming and stabilizing ER structure, 3 and a Yale School of Medicine group led by William Sessa showed that NOGO-B is highly expressed in lung tissue and regulates nonpathological vascular remodeling. [4][5][6] Sessa is a professor of pharmacology at Yale. Another Sessa-led study in 2010 showed that Nogo-b was downregulated in lung tissue but upregulated in pulmonary vasculature in mouse models of asthma, 7 which highlighted a NOGO-B-related mechanism that appeared to be specific to pulmonary blood vessels.…”

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confidence: 99%

NOGO could go far

Haas¹

2011

Science-Business eXchange

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A team of U.S. and Canadian researchers has shown that blocking production of NOGO-B in pulmonary arteries could prevent the deleterious vascular remodeling seen in pulmonary arterial hypertension. 1 If future studies demonstrate that NOGO-B inhibitors could treat disease that already is established, the compounds could become the first disease modifiers for pulmonary arterial hypertension, which currently is treated with vasodilators that alleviate disease symptoms but do not address underlying causes.In pulmonary arterial hypertension (PAH), increased proliferation and resistance to apoptosis in pulmonary vasculature-but not in systemic vasculature-results in obstruction of the pulmonary arteries, hypertension, right ventricular hypertrophy and eventual death.Last year, researchers from the University of Alberta and Metabolic Modulators Research Ltd. reported in Science Translational Medicine that in mouse models of hypoxia-induced PAH, a metabolic shift from glucose oxidation to glycolysis in pulmonary arterial cells drove the proliferative, antiapoptotic phenotype seen in PAH. 2 However, the team did not identify the mechanism underlying the change in metabolism.Evangelos Michelakis, who was corresponding author on both the 2010 study and the new paper, told SciBX the same metabolic shift occurs in nonhypoxic PAH models and human diseases such as idiopathic PAH, familial PAH associated with mutations in bone morphogenic protein receptor type II (BMPRII), scleroderma Figure 1. NOGO-B: on a stressful pathway to pulmonary arterial hypertension. in pulmonary artery smooth muscle cells, hypoxia induces endoplasmic reticulum (er) stress and expression of activating transcription factor 6 (atF6) [a], which upregulates the nOgO-B isoform of reticulon 4 (rtn4; nOgO; nOgO-a). increased levels of nOgO-B disrupt the spatial proximity and normal interactions between the er and mitochondria [b] to increase cytosolic glycolysis and decrease glucose oxidation [c], which promote cell proliferation and resistance to apoptosis [d], respectively, and lead to the deleterious vascular remodeling seen in pulmonary arterial hypertension (Pah). 2,10 Axerion Therapeutics Inc. has reticulon 4 receptor (rtn4r; ngr) decoys that bind nOgO and two other ngr ligands in preclinical development to treat spinal cord injury (sci).

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Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells

Abstract: Nogo isoforms (Nogo-A

Cited by 132 publications

References 15 publications

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

A Lettuce (Lactuca sativa) Homolog of Human Nogo-B Receptor Interacts with cis-Prenyltransferase and Is Necessary for Natural Rubber Biosynthesis

NOGO could go far

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