Structure and function of VEGF receptors

Stuttfeld, Edward; Ballmer-Hofer, Kurt

doi:10.1002/iub.234

Cited by 189 publications

(139 citation statements)

References 98 publications

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“…The very low sequence conservation for IFNAR1 is in line with the findings of this study that the TMD and its immediate surroundings serve merely as a bridge between the extracellular and cytoplasmic domain that does not convey a structural signal. This is fundamentally different from the suggested mechanism of EPOR, IL6R2, and VEGFR2 activation, where ligand-induced structural perturbations of the intracellular domains were suggested to play a key role in signaling (26,28,32).…”

Section: Sequence Conservation Of Tmds and Their Surroundings-contrasting

confidence: 73%

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

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Type I interferons serve as the first line of defense against pathogen invasion. Binding of IFNs to its receptors, IFNAR1 and IFNAR2, is leading to activation of the IFN response. To determine whether structural perturbations observed during binding are propagated to the cytoplasmic domain, multiple mutations were introduced into the transmembrane helix and its surroundings. Insertion of one to five alanine residues near either the N or C terminus of the transmembrane domain (TMD) likely promotes a rotation of 100°and a translation of 1.5 Å per added residue. Surprisingly, the added alanines had little effect on the binding affinity of IFN to the cell surface receptors, STAT phosphorylation, or gene induction. Similarly, substitution of the juxtamembrane residues of the TMD with alanines, or replacement of the TMD of IFNAR1 with that of IFNAR2, did not affect IFN binding or activity. Finally, only the addition of 10 serine residues (but not 2 or 4) between the extracellular domain of IFNAR1 and the TMD had some effect on signaling. Bioinformatic analysis shows a correlation between high sequence conservation of TMDs of cytokine receptors and the ability to transmit structural signals. Sequence conservation near the TMD of IFNAR1 is low, suggesting limited functional importance for this region. Our results suggest that IFN binding to the extracellular domains of IFNAR1 and IFNAR2 promotes proximity between the intracellular domains and that differential signaling is a function of duration of activation and affinity of binding rather than specific conformational changes transmitted from the outside to the inside of the cell.Type I interferons (IFNs) orchestrate the antiviral innate immunity in vertebrates. They consist of 16 members in humans as follows: 12 different IFN␣ subtypes, as well as IFN␤, IFN, IFN⑀, and IFN. They are clustered on the short arm of chromosome 9. All type I interferons elicit their innate and adaptive immune responses after binding to the receptor and forming the IFNAR1-IFN-IFNAR2 ternary complex (1, 2), the formation of which is essential for signaling. Both IFNAR1 and IFNAR2 belong to the class II helical cytokine receptors with four fibronectin type III-like subdomains for IFNAR1 and two subdomains for IFNAR2. The extracellular domains are followed by a single helix of 21 amino acids spanning the membrane, which in turn is connected to mostly natively unstructured intracellular domains and their associated effectors (Fig. 1A) (3). Cells lacking one of the receptors lack normal IFN signaling (4, 5). Structurally different members of type I IFNs bind to the same cell surface receptor but mediate differential responses that result from differences in binding affinities, concentration of IFN, and duration of activation (5-13). Differential signaling is realized through robust (antiviral) versus tunable (antiproliferative and immunomodulatory) gene induction leading to different phenotypic outcomes (14,15). Receptor dimerization drives the activation of cytosolic associated Janus family kina...

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Section: Sequence Conservation Of Tmds and Their Surroundings-contrasting

confidence: 73%

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

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“…However, in the chick chorioallantoic membrane (CAM) model of angiogenesis, tetrac and nanotetrac block the actions of VEGF and bFGF in the absence of agonist iodothyronines T 4 and T 3 . The molecular basis of this anti-angiogenic quality of tetrac has not been established, but the complexing ofv3 with VEGFR (VEGF receptor) (Somananth et al, 2009), a receptor tyrosine kinase (Stuttfeld & Ballmer-Hofer, 2009), is reproduced with other growth factor receptors, such as PDGFR (Borges et al, 2000), and perhaps with EGFR (Jones et al, 1997). Such complexing of the integrin with growth factor receptors may be via the cytoplasmic domains of the protein (VEGFR2) (Somananth et al, 2009) or extracellular domains (PDGFR) (Borges et al, 2000).…”

Section: Disruption By Tetrac Of Crosstalk Between Integrin V3 and mentioning

confidence: 99%

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

Lin

Tang

Davis

et al. 2012

CCO

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Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation induce apoptosis in cancer cells, oppose angiogenesis about xenografted human tumors and block cancer cell repair of double-stranded DNA breaks. These nongenomic actions of tetrac are initiated at a tetrac-thyroid hormone receptor on plasma membrane integrin v3. In this review, we examine additional anti-cancer activities of tetrac formulations at v3 and what is known about their mechanisms. These activities include 1) reversal of cancer cell chemoresistance (= induction of chemosensitization) and 2) disruption of crosstalk between v3 and nearby cell surface growth factor receptors. In addition, nanoparticulate tetrac 3) alters expression of differentially-regulated inflammation-relevant genes that may be important to inflammation-supported cancer. For example, the agent downregulates genes whose products mediate cytokine responses and upregulates suppressor of cytokine signaling, SOCS4. Such actions of tetrac formulations define a multi-target functional profile, although the activities of tetrac begin at a single anatomic plasma membrane receptor on integrin v3.

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“…This enhances the release of nitric oxide (NO) which extends and increases the permeability of the vessel, which is vital for the start of angiogenesis. VEGF also acts through the receptor VEGFR1 (Fms-like tyrosine kinase-1 (Flt-1)), which, in response, generates vascular sprouting (Barańska et al, 2005;Stuttfeld and Ballmer-Hofer, 2009). …”

Section: Introductionmentioning

confidence: 99%

A preliminary evaluation of VEGF-A, VEGFR1 and VEGFR2 in patients with well-controlled type 2 diabetes mellitus

Ruszkowska-Ciastek

Sokup

Socha

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Decompensated chronic hyperglycemia often leads to late microvascular complications such as retinopathy, diabetic foot syndrome, and diabetic kidney disease. The aim of this study was to determine the concentration of vascular endothelial growth factor A (VEGF-A) and its receptors in patients with well-controlled diabetes. Methods: The study was conducted on 31 patients with well-controlled type 2 diabetes without micro-or macroangiopathy. Thirty healthy volunteers were enrolled in a control group. Serum concentrations of VEGF-A, VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), fasting glucose, and lipid profiles were measured, and the plasma concentration of glycated hemoglobin (HbA1c) was determined. Results: No significant differences were observed between the concentration of VEGF-A, VEGFR1 or VEGFR2 in the subject group and that in the control group. Positive correlations were noted between the levels of VEGF-A, VEGFR2, and triglyceride, and there was a negative correlation between the levels of VEGFR2 and high-density lipoprotein (HDL)-cholesterol in the study group. Conclusions: The concentrations of VEGF-A and its receptors 1 and 2 in patients with well-controlled diabetes are comparable to those of healthy individuals, which may indicate that appropriate control of glucose levels delays the occurrence of vascular complications. A negative correlation between VEGFR2 and HDL-cholesterol levels, and positive correlations between VEGF-A, VEGFR2, and triglyceride levels, suggest that lipid abnormalities occurring in diabetes may be involved in the modulation of angiogenesis.

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Structure and function of VEGF receptors

Cited by 189 publications

References 98 publications

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

A preliminary evaluation of VEGF-A, VEGFR1 and VEGFR2 in patients with well-controlled type 2 diabetes mellitus

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