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PMID:20660291

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Citation

Mitola, S, Ravelli, C, Moroni, E, Salvi, V, Leali, D, Ballmer-Hofer, K, Zammataro, L and Presta, M (2010) Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 116:3677-80

Abstract

The bone morphogenic protein antagonist gremlin is expressed during embryonic development and under different pathologic conditions, including cancer. Gremlin is a proangiogenic protein belonging to the cystine-knot superfamily that includes transforming growth factor-β proteins and the angiogenic vascular endothelial growth factors (VEGFs). Here, we demonstrate that gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals, in a bone morphogenic protein-independent manner. Similar to VEGF-A, gremlin activates VEGFR2 in endothelial cells, leading to VEGFR2-dependent angiogenic responses in vitro and in vivo. Gremlin thus represents a novel proangiogenic VEGFR2 agonist distinct from the VEGF family ligands with implications in vascular development, angiogenesis-dependent diseases, and tumor neovascularization.

Links

PubMed Online version:10.1182/blood-2010-06-291930

Keywords

Animals; Cattle; Cell Line; Chickens; Endothelial Cells/cytology; Endothelial Cells/metabolism; Humans; Intercellular Signaling Peptides and Proteins/metabolism; Mice; Neoplasms/metabolism; Neovascularization, Pathologic/metabolism; Vascular Endothelial Growth Factor Receptor-2/agonists; Vascular Endothelial Growth Factor Receptor-2/metabolism

Significance

Annotations

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

HUMAN:GREM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968

F

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:0002092: positive regulation of receptor internalization

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P35918)

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:1900086: positive regulation of peptidyl-tyrosine autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P35918)

Seeded From UniProt

complete

HUMAN:VEGFA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17948

F

Seeded From UniProt

complete

HUMAN:VEGFA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968

F

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0002092: positive regulation of receptor internalization

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P35918)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:1900086: positive regulation of peptidyl-tyrosine autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P35918)

Seeded From UniProt

complete

HUMAN:VGFR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692

F

Seeded From UniProt

complete

HUMAN:VGFR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49763

F

Seeded From UniProt

complete

MOUSE:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692

F

Seeded From UniProt

complete

MOUSE:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O70326

F

Seeded From UniProt

complete

MOUSE:VGFR2

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VGFR2

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60565

F

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692

F

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O70326

F

Seeded From UniProt

complete

HUMAN:PLGF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17948

F

Seeded From UniProt

complete

MOUSE:VGFR2

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:VGFR2

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VGFR2

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VGFR2

involved_in

GO:0038083: peptidyl-tyrosine autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

enables

GO:0048018: receptor ligand activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35918

F

Seeded From UniProt

complete

HUMAN:VEGFA

enables

GO:0043184: vascular endothelial growth factor receptor 2 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968-2

F

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:1900086: positive regulation of peptidyl-tyrosine autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P35918)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0002092: positive regulation of receptor internalization

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P35918)

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0038085: vascular endothelial growth factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692

F

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968

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

involved_in

GO:0002092: positive regulation of receptor internalization

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P35918)

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:0007165: signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GREM1

enables

GO:0030297: transmembrane receptor protein tyrosine kinase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:GREM1

enables

GO:0043184: vascular endothelial growth factor receptor 2 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968-2

F

Seeded From UniProt

complete

MOUSE:GREM1

enables

GO:0048018: receptor ligand activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35918

F

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:1900086: positive regulation of peptidyl-tyrosine autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P35918)

Seeded From UniProt

complete

MOUSE:GREM1

involved_in

GO:2000273: positive regulation of signaling receptor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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Have any questions? Please email us at ecoliwiki@gmail.com

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Backtrace:

#0 /usr/local/github/wiki-extensions/wiki-extensions-hulab/AnnotationLinks/AnnotationLinks.php(70): AnnotationLinks::getQuickGOannotations(string, array)
#1 /var/www/html/go/wiki/includes/parser/Parser.php(3888): AnnotationLinks::renderAnnotations(NULL, array, Parser, PPFrame_DOM)
#2 /var/www/html/go/wiki/includes/parser/Preprocessor_DOM.php(1362): Parser->extensionSubstitution(array, PPFrame_DOM)
#3 /var/www/html/go/wiki/includes/parser/Parser.php(2942): PPFrame_DOM->expand(DOMElement, integer)
#4 /var/www/html/go/wiki/includes/parser/Parser.php(1293): Parser->replaceVariables(string)
#5 /var/www/html/go/wiki/includes/parser/Parser.php(443): Parser->internalParse(string)
#6 /var/www/html/go/wiki/includes/content/WikitextContent.php(323): Parser->parse(string, Title, ParserOptions, boolean, boolean, integer)
#7 /var/www/html/go/wiki/includes/content/AbstractContent.php(516): WikitextContent->fillParserOutput(Title, integer, ParserOptions, boolean, ParserOutput)
#8 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(231): AbstractContent->getParserOutput(Title, integer, ParserOptions, boolean)
#9 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(126): RefreshLinksJob->runForTitle(Title)
#10 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(296): RefreshLinksJob->run()
#11 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(193): JobRunner->executeJob(RefreshLinksJob, Wikimedia\Rdbms\LBFactorySimple, BufferingStatsdDataFactory, integer)
#12 /var/www/html/go/wiki/includes/MediaWiki.php(1002): JobRunner->run(array)
#13 /var/www/html/go/wiki/includes/MediaWiki.php(988): MediaWiki->triggerSyncJobs(integer, MediaWiki\Logger\LegacyLogger)
#14 /var/www/html/go/wiki/includes/MediaWiki.php(912): MediaWiki->triggerJobs()
#15 /var/www/html/go/wiki/includes/MediaWiki.php(727): MediaWiki->restInPeace(string, boolean)
#16 /var/www/html/go/wiki/includes/MediaWiki.php(750): MediaWiki->{closure}()
#17 /var/www/html/go/wiki/includes/MediaWiki.php(557): MediaWiki->doPostOutputShutdown(string)
#18 /var/www/html/go/wiki/index.php(42): MediaWiki->run()
#19 {main}

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