Thrombospondins: from structure to therapeutics

Isenberg, Jeff S.; Frazier, William A.; Roberts, D. A.

doi:10.1007/s00018-007-7488-x

Cited by 118 publications

(67 citation statements)

References 133 publications

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“…Several receptors of TSP1 have been implicated in its antiangiogenic activity (11,31,46), but their functions may be distinct. CD36 is necessary for TSP1 to inhibit FGF2-stimulated angiogenesis in rat cornea (13), but it is not clear that this requirement extends to VEGF-stimulated angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

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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%

“…Ligation of CD47 Is Sufficient to Inhibit VEGFR2 Phosphorylation-TSP1 inhibits endothelial cell NO/cGMP signaling via CD47 at Ն10 pM concentrations (31). To explore the possibility that TSP1 also regulates VEGFR2 phosphorylation via CD47, we first used the TSP1-derived CD47-binding peptide 7N3 (FIRVVMYEGKK).…”

Section: Tsp1mentioning

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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“…Ser 64 of CD47 Is Essential for Inhibiting T Cell ActivationPrevious studies have shown that TSP1 inhibits T cell activation induced by antibody engagement of the T cell receptor component CD3 (26,27). Activation of WT Jurkat cells using CD3 antibody increased expression of mRNA for the early activation marker CD69 by 80-fold at 2 h (Fig.…”

Section: Cd47 Is Modified With Heparan and Chondroitin Sulfatementioning

confidence: 91%

“…Identification of GAG Modification Sites on CD47-Based on the previously defined amino acid sequence parameters for GAG modification (52) and a crystal structure for the recombinant extracellular domain of CD47 (53), we identified Ser 64 and Ser 79 as surface-exposed residues that could be potential acceptors for GAG addition (Fig. 7E).…”

Section: Cd47 Is Modified With Heparan and Chondroitin Sulfatementioning

confidence: 98%

“…To investigate whether these residues are involved in CD47 modification, we mutated each Ser residue to Ala in an expression plasmid encoding an internal FLAG-tagged CD47. We transiently expressed these constructs in JinB8 cells and found that mutation of Ser 64 or Ser 79 greatly diminished expression of the high molecular weight isoform of CD47 (Fig. 7D).…”

Section: Cd47 Is Modified With Heparan and Chondroitin Sulfatementioning

confidence: 99%

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Heparan Sulfate Modification of the Transmembrane Receptor CD47 Is Necessary for Inhibition of T Cell Receptor Signaling by Thrombospondin-1

Kaur

Кузнецова

Pendrak

et al. 2011

Journal of Biological Chemistry

110

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Cell surface proteoglycans on T cells contribute to retroviral infection, binding of chemokines and other proteins, and are necessary for some T cell responses to the matricellular glycoprotein thrombospondin-1. The major cell surface proteoglycans expressed by primary T cells and Jurkat T cells have an apparent M r > 200,000 and are modified with chondroitin sulfate and heparan sulfate chains. Thrombospondin-1 bound in a heparin-inhibitable manner to this proteoglycan and to a soluble form released into the medium. Based on mass spectrometry, knockdown, and immunochemical analyses, the proteoglycan contains two major core proteins as follows: amyloid precursor-like protein-2 (APLP2, apparent M r 230,000) and CD47 (apparent M r > 250,000). CD47 is a known thrombospondin-1 receptor but was not previously reported to be a proteoglycan. This proteoglycan isoform of CD47 is widely expressed on vascular cells. Mutagenesis identified glycosaminoglycan modification of CD47 at Ser 64 and Ser 79 . Inhibition of T cell receptor signaling by thrombospondin-1 was lost in CD47-deficient T cells that express the proteoglycan isoform of APLP2, indicating that binding to APLP2 is not sufficient. Inhibition of CD69 induction was restored in CD47-deficient cells by re-expressing CD47 or an S79A mutant but not by the S64A mutant. Therefore, inhibition of T cell receptor signaling by thrombospondin-1 is mediated by CD47 and requires its modification at Ser 64 .Cell surface proteoglycans play critical roles in cell-matrix interactions. They act as co-receptors for some pathogens and growth and motility factors and regulate the functions of other cell surface signaling receptors (reviewed in Refs. 1-4). Chondroitin sulfate or heparan sulfate chains are attached through a conserved core oligosaccharide sequence to specific Ser residues on the core proteins (5). The most prevalent cell surface heparan sulfate proteoglycans (HSPG) 5 are the syndecans and glypicans, but a number of additional cell surface proteins can be specifically modified with heparan sulfate glycosaminoglycans (GAG) in certain cells and tissues (6). CD4 ϩ T cells express highly sulfated heparan sulfate chains because of their high expression of the N-deacetylase/N-sulfotransferase NDST2 and the 3-O-sulfotransferases 3-OST3 (7). T cell HSPGs have been identified as receptors for histones (8) and cyclophilin B (9, 10) and serve as co-receptors for heparinbinding chemokines such as regulated on activation normal T cell expressed and secreted (RANTES) (11).T cell HSPGs are also co-receptors for retroviral infection. An unidentified cell surface HSPG expressed by the H9 T cell line interacts with the V3 region of the HIV1 envelope gp120-gp41, and heparitinase treatment inhibited binding and entry of the virus into H9 cells (12). The fusion peptide domain of gp41 also interacts specifically with an HSPG on T cells (13). A subsequent study concluded that syndecan functions in trans to promote HIV infection of T cells (14). Similar HSPG binding was demonstrated for the hu...

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Systems Biology to Study Platelet‐Related Bleeding Disorders

Akkerman

Bono

2011

Platelet Proteomics

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Thrombospondins: from structure to therapeutics

Cited by 118 publications

References 133 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

Heparan Sulfate Modification of the Transmembrane Receptor CD47 Is Necessary for Inhibition of T Cell Receptor Signaling by Thrombospondin-1

Systems Biology to Study Platelet‐Related Bleeding Disorders

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