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

アクセス数:809件（2025-10-24 06:03 集計）

固定URL: https://hdl.handle.net/11094/71420

閲覧可能ファイル

ファイル	フォーマット	利用条件	サイズ	閲覧回数	利用開始日	説明	information
JBC_2011_25947_62	pdf	なし	9.49 MB	239	2019.03.20

論文情報

ファイル出力 EndNote Basic出力 Mendeley出力

タイトル	Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) : A DUAL RECEPTOR ANTAGONISM
著者	著者名 Goyal, Atul
	著者名 Pal, Nutan
	著者名 Concannon, Matthew
	著者名 Paul, Matthew
	著者名 Doran, Mike
	著者名 Poluzzi, Chiara
	NRID 1000050187845 1000050187845 researchmap permalink read0054833 read0054833 Scopus Author ID 7201662709 7201662709 ORCID 0000-0002-6433-1410 0000-0002-6433-1410 著者名 Sekiguchi, Kiyotoshi
	著者名 Whitelock, John M.
	著者名 Neill, Thomas
	著者名 Iozzo, Renato V.
内容	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
抄録	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.
出版者	American Society for Biochemistry and Molecular Biology
収録物名	Journal of Biological Chemistry
巻(号)	286(29)
ページ	25947-25962
刊行年月	2011-07
言語	英語
ハンドルURL	https://hdl.handle.net/11094/71420
eISSN	1083351X
NCID	AA1202441X
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1074/jbc.M111.243626
アクセス権	open access
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	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	英語
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	英語
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

閲覧可能ファイル

論文情報

論文詳細を表示