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PMID:17077323

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Citation

Stabile, H, Mitola, S, Moroni, E, Belleri, M, Nicoli, S, Coltrini, D, Peri, F, Pessi, A, Orsatti, L, Talamo, F, Castronovo, V, Waltregny, D, Cotelli, F, Ribatti, D and Presta, M (2007) Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor. Blood 109:1834-40

Abstract

Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes during growth, differentiation, and development by heterodimerizing various BMPs. Here, we identify Drm/gremlin as a novel proangiogenic factor expressed by endothelium. Indeed, Drm/gremlin was purified to homogeneity from the conditioned medium of transformed endothelial cells using an endothelial-cell sprouting assay to follow protein isolation. Accordingly, recombinant Drm/gremlin stimulates endothelial-cell migration and invasion in fibrin and collagen gels, binds with high affinity to various endothelial cell types, and triggers tyrosine phosphorylation of intracellular signaling proteins. Also, Drm/gremlin induces neovascularization in the chick embryo chorioallantoic membrane. BMP4 does not affect Drm/gremlin interaction with endothelium, and both molecules exert a proangiogenic activity in vitro and in vivo when administered alone or in combination. Finally, Drm/gremlin is produced by the stroma of human tumor xenografts in nude mice, and it is highly expressed in endothelial cells of human lung tumor vasculature when compared with non-neoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis.

Links

PubMed Online version:10.1182/blood-2006-06-032276

Keywords

Amino Acid Sequence; Angiogenesis Inducing Agents/chemistry; Angiogenesis Inducing Agents/isolation & purification; Angiogenesis Inducing Agents/metabolism; Angiogenesis Inducing Agents/pharmacology; Animals; Bone Morphogenetic Proteins/antagonists & inhibitors; Bone Morphogenetic Proteins/metabolism; Cells, Cultured; Chick Embryo; Endothelial Cells/metabolism; Immunohistochemistry; Intercellular Signaling Peptides and Proteins/chemistry; Intercellular Signaling Peptides and Proteins/isolation & purification; Intercellular Signaling Peptides and Proteins/metabolism; Intercellular Signaling Peptides and Proteins/pharmacology; Mice; Molecular Sequence Data; Neoplasms/blood supply; Neoplasms/genetics; Neoplasms/metabolism; Neoplasms/pathology; Protein Binding; Signal Transduction/drug effects; Xenograft Model Antitumor Assays

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:GREM1

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GREM1

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GREM1

enables

GO:0043395: heparan sulfate proteoglycan binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GREM1

part_of

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GREM1

colocalizes_with

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:0043542: endothelial cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:0051893: regulation of focal adhesion assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:0061098: positive regulation of protein tyrosine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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