Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM

Goyal, Atul; Pal, Nutan; Concannon, Matthew; Paul, Matthew; Doran, Mike; Poluzzi, Chiara; Sekiguchi, Kiyotoshi; Whitelock, John M.; Neill, Thomas; Iozzo, Renato V.

doi:https://doi.org/10.1074/jbc.M111.243626

Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM

Goyal, Atul; Pal, Nutan; Concannon, Matthew et al.

Journal of Biological Chemistry, 2011, 286(29), 25947-25962

Number of Access:692（2025-08-18 12:36 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/71420

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Title	Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM
Creator	CreatorName Goyal, Atul
	CreatorName Pal, Nutan
	CreatorName Concannon, Matthew
	CreatorName Paul, Matthew
	CreatorName Doran, Mike
	CreatorName Poluzzi, Chiara
	NRID 1000050187845 1000050187845 researchmap permalink read0054833 read0054833 Scopus Author ID 7201662709 7201662709 ORCID 0000-0002-6433-1410 0000-0002-6433-1410 CreatorName Sekiguchi, Kiyotoshi
	CreatorName Whitelock, John M.
	CreatorName Neill, Thomas
	CreatorName Iozzo, Renato V.
Description	This research was originally published in the Journal of Biological Chemistry. Atul Goyal, Nutan Pal, Matthew Concannon, Matthew Paul, Mike Doran, Chiara Poluzzi, Kiyotoshi Sekiguchi, John M. Whitelock, Thomas Neill, and Renato V. Iozzo. Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM. J. Biol. Chem. 2011; 286: 25947-25962 © the American Society for Biochemistry and Molecular Biology
Abstract	Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the α2β1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the α2β1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the α2β1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express α2β1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.
Publisher	American Society for Biochemistry and Molecular Biology
Source Title	Journal of Biological Chemistry
Volume (Issue)	286(29)
Page	25947-25962
Date of Issued	2011-07
Language	English
Handle URL	https://hdl.handle.net/11094/71420
eISSN	1083351X
NCID	AA1202441X
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1074/jbc.M111.243626
Access Rights	open access
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Journal of Biological Chemistry. 2011, 286(29), p. 25947-25962
DC.title	Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM
DC.creator	Goyal, Atul
	Pal, Nutan
	Concannon, Matthew
	Paul, Matthew
	Doran, Mike
	Poluzzi, Chiara
	Sekiguchi, Kiyotoshi
	Whitelock, John M.
	Neill, Thomas
	Iozzo, Renato V.
DC.publisher	American Society for Biochemistry and Molecular Biology
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2011-07
DC.identifier	https://doi.org/10.1074/jbc.M111.243626
DC.description	This research was originally published in the Journal of Biological Chemistry. Atul Goyal, Nutan Pal, Matthew Concannon, Matthew Paul, Mike Doran, Chiara Poluzzi, Kiyotoshi Sekiguchi, John M. Whitelock, Thomas Neill, and Renato V. Iozzo. Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM. J. Biol. Chem. 2011; 286: 25947-25962 © the American Society for Biochemistry and Molecular Biology
DCTERMS.abstract	Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the α2β1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the α2β1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the α2β1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express α2β1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.
DC.format	71420
citation_title	Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM
citation_author	Goyal, Atul
	Pal, Nutan
	Concannon, Matthew
	Paul, Matthew
	Doran, Mike
	Poluzzi, Chiara
	Sekiguchi, Kiyotoshi
	Whitelock, John M.
	Neill, Thomas
	Iozzo, Renato V.
citation_publisher	American Society for Biochemistry and Molecular Biology
citation_language	English
citation_date	2011-07
citation_journal_title	Journal of Biological Chemistry
citation_volume	286
citation_issue	29
citation_firstpage	25947
citation_lastpage	25962
citation_doi	https://doi.org/10.1074/jbc.M111.243626
citation_public_url	https://hdl.handle.net/11094/71420

Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM

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