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Minimal active doma...
Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein
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- Dixelius, Johan (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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- Olsson, Anna-Karin (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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- Thulin, Åsa (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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- Lee, Chunsik (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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- Johansson, Irja (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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- Claesson-Welsh, Lena (författare)
- Uppsala universitet,Institutionen för genetik och patologi
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(creator_code:org_t)
- 2006
- 2006
- Engelska.
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 66:4, s. 2089-97
- Relaterad länk:
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http://www.ncbi.nlm....
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline-rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/proline-rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate alpha-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving alpha(v)beta3 integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility.
Nyckelord
- Actinin/metabolism
- Amino Acid Sequence
- Animals
- Cattle
- Cell Movement/drug effects/physiology
- Endothelial Cells/cytology/*drug effects
- Focal Adhesion Protein-Tyrosine Kinases/metabolism
- Integrin alphaVbeta3/metabolism
- Molecular Sequence Data
- Neovascularization; Physiologic/*drug effects
- Paxillin/antagonists & inhibitors/biosynthesis
- Peptide Fragments/chemistry/*pharmacology
- Phosphorylation/drug effects
- Protein Structure; Tertiary
- Protein-Serine-Threonine Kinases/metabolism
- Proteins/chemistry/*pharmacology
- Research Support; Non-U.S. Gov't
- Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism/pharmacology
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- MEDICINE
- MEDICIN
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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