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Article: Suppression of the Raf/MEK/ERK Signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4

TitleSuppression of the Raf/MEK/ERK Signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4
Authors
KeywordsAngiogenesis
Angiopoietin-like proteins
Glycosylation
MAP kinase
Neovascularization
Issue Date2008
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.lww.com/product/?1079-5642
Citation
Arteriosclerosis, Thrombosis, And Vascular Biology, 2008, v. 28 n. 5, p. 835-840 How to Cite?
AbstractOBJECTIVES - Angiopoietin-like protein 4 (Angptl4) is a secreted glycoprotein that has recently been implicated in the regulation of angiogenesis and metastasis. This study aimed to investigate the structural and cellular basis underlying the biological actions of Angptl4. METHODS AND RESULTS - Circulating Angptl4 was proteolytically cleaved into NH2-terminal coiled-coil domain (N-Angptl4) and COOH-terminal fibrinogen-like domain (C-Angptl4). Using amino acid sequencing analysis, we identified a major cleavage site between Lys and Leu and a minor cleavage site between Lys and Met in mouse Angptl4. C-Angptl4, but not N-Angptl4, potently inhibited both bFGF- and VEGF-induced cell proliferation, migration, and tubule formation in endothelial cells, and prevented neovascularization in mice. Treatment of C-Angptl4 with PNGase F (an N-glycosidase) ablated its N-linked glycosylation, and also significantly attenuated its antiangiogenic activities. C-Angptl4 blocked bFGF-induced activation of ERK1/2 MAP kinase, but had no obvious effect on Akt and P38 MAP kinase. Furthermore, C-Angptl4 abrogated bFGF-induced phosphorylation of Raf-1 and MEK1/2, whereas neither auto-phosphorylation of FGF receptor-1 nor activation of Ras was affected, suggesting that the blockage occurs at the level of Raf-1 activation. CONCLUSIONS - The carboxyl terminus of Angptl4 alone is sufficient to suppress angiogenesis, possibly through inhibiting the Raf/MEK/ERK1/2 MAP kinase pathway in endothelial cells. © 2008 American Heart Association, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/76687
ISSN
2015 Impact Factor: 5.969
2015 SCImago Journal Rankings: 3.356
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYang, YHen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorLam, KSLen_HK
dc.contributor.authorYau, MHen_HK
dc.contributor.authorCheng, KKYen_HK
dc.contributor.authorZhang, Jen_HK
dc.contributor.authorZhu, Wen_HK
dc.contributor.authorWu, Den_HK
dc.contributor.authorXu, Aen_HK
dc.date.accessioned2010-09-06T07:23:52Z-
dc.date.available2010-09-06T07:23:52Z-
dc.date.issued2008en_HK
dc.identifier.citationArteriosclerosis, Thrombosis, And Vascular Biology, 2008, v. 28 n. 5, p. 835-840en_HK
dc.identifier.issn1079-5642en_HK
dc.identifier.urihttp://hdl.handle.net/10722/76687-
dc.description.abstractOBJECTIVES - Angiopoietin-like protein 4 (Angptl4) is a secreted glycoprotein that has recently been implicated in the regulation of angiogenesis and metastasis. This study aimed to investigate the structural and cellular basis underlying the biological actions of Angptl4. METHODS AND RESULTS - Circulating Angptl4 was proteolytically cleaved into NH2-terminal coiled-coil domain (N-Angptl4) and COOH-terminal fibrinogen-like domain (C-Angptl4). Using amino acid sequencing analysis, we identified a major cleavage site between Lys and Leu and a minor cleavage site between Lys and Met in mouse Angptl4. C-Angptl4, but not N-Angptl4, potently inhibited both bFGF- and VEGF-induced cell proliferation, migration, and tubule formation in endothelial cells, and prevented neovascularization in mice. Treatment of C-Angptl4 with PNGase F (an N-glycosidase) ablated its N-linked glycosylation, and also significantly attenuated its antiangiogenic activities. C-Angptl4 blocked bFGF-induced activation of ERK1/2 MAP kinase, but had no obvious effect on Akt and P38 MAP kinase. Furthermore, C-Angptl4 abrogated bFGF-induced phosphorylation of Raf-1 and MEK1/2, whereas neither auto-phosphorylation of FGF receptor-1 nor activation of Ras was affected, suggesting that the blockage occurs at the level of Raf-1 activation. CONCLUSIONS - The carboxyl terminus of Angptl4 alone is sufficient to suppress angiogenesis, possibly through inhibiting the Raf/MEK/ERK1/2 MAP kinase pathway in endothelial cells. © 2008 American Heart Association, Inc.en_HK
dc.languageengen_HK
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.lww.com/product/?1079-5642en_HK
dc.relation.ispartofArteriosclerosis, Thrombosis, and Vascular Biologyen_HK
dc.rightsArteriosclerosis, Thrombosis, and Vascular Biology. Copyright © Lippincott Williams & Wilkins.en_HK
dc.subjectAngiogenesis-
dc.subjectAngiopoietin-like proteins-
dc.subjectGlycosylation-
dc.subjectMAP kinase-
dc.subjectNeovascularization-
dc.subject.meshAmino Acid Sequenceen_HK
dc.subject.meshAngiopoietinsen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBlood Proteins - physiologyen_HK
dc.subject.meshCell Lineen_HK
dc.subject.meshCell Movement - drug effectsen_HK
dc.subject.meshCell Proliferation - drug effectsen_HK
dc.subject.meshEndothelium, Vascular - drug effects - pathologyen_HK
dc.subject.meshExtracellular Signal-Regulated MAP Kinases - antagonists & inhibitors - metabolismen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshFibroblast Growth Factor 2 - pharmacologyen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMAP Kinase Kinase Kinases - antagonists & inhibitors - metabolismen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Inbred C57BLen_HK
dc.subject.meshMice, Nudeen_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshNeovascularization, Physiologic - physiologyen_HK
dc.subject.meshPhosphorylation - drug effectsen_HK
dc.subject.meshSignal Transductionen_HK
dc.subject.meshVascular Endothelial Growth Factor A - pharmacologyen_HK
dc.subject.meshraf Kinases - antagonists & inhibitors - metabolismen_HK
dc.titleSuppression of the Raf/MEK/ERK Signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1079-5642&volume=28&spage=835&epage=840&date=2008&atitle=Suppression+Of+The+Raf/mek/erk+Signaling+Cascade+And+Inhibition+Of+Angiogenesis+By+The+Carboxyl+Terminus+Of+Angiopoietin-like+Protein+4en_HK
dc.identifier.emailWang, Y:yuwanghk@hku.hken_HK
dc.identifier.emailLam, KSL:ksllam@hku.hken_HK
dc.identifier.emailXu, A:amxu@hkucc.hku.hken_HK
dc.identifier.authorityWang, Y=rp00239en_HK
dc.identifier.authorityLam, KSL=rp00343en_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1161/ATVBAHA.107.157776en_HK
dc.identifier.pmid18340008-
dc.identifier.scopuseid_2-s2.0-42149108104en_HK
dc.identifier.hkuros157713en_HK
dc.identifier.hkuros146088-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-42149108104&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume28en_HK
dc.identifier.issue5en_HK
dc.identifier.spage835en_HK
dc.identifier.epage840en_HK
dc.identifier.isiWOS:000255056700011-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYang, YH=7409390524en_HK
dc.identifier.scopusauthoridWang, Y=34973733700en_HK
dc.identifier.scopusauthoridLam, KSL=8082870600en_HK
dc.identifier.scopusauthoridYau, MH=9233223900en_HK
dc.identifier.scopusauthoridCheng, KKY=7402997599en_HK
dc.identifier.scopusauthoridZhang, J=35504391800en_HK
dc.identifier.scopusauthoridZhu, W=7404232544en_HK
dc.identifier.scopusauthoridWu, D=7404297751en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK

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