| The angiotensin IV analog Nle-Tyr-Leu-psi-(CH2-NH2)3-4-His-Pro-Phe (norleual) can act as a hepatocyte growth factor/c-Met inhibitor. | |
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MedLine Citation:
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PMID: 20086056 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The angiotensin (Ang) IV analog norleual [Nle-Tyr-Ile-psi-(CH2-NH2)(3-4)-His-Pro-Phe] exhibits structural homology with the hinge (linker) region of hepatocyte growth factor (HGF) and is hypothesized to act as a hinge region mimic. Norleual competitively inhibited the binding of HGF to its receptor c-Met in mouse liver membranes, with an IC(50) value of 3 pM. Predictably, norleual was able to inhibit HGF-dependent signaling, proliferation, migration, and invasion in multiple cell types at concentrations in the picomolar range. Ex vivo studies demonstrated that norleual exhibited potent antiangiogenic activity, an attribute that would be predicted for a HGF/c-Met antagonist. Furthermore, norleual suppressed pulmonary colonization by B16-F10 murine melanoma cells, which are characterized by an overactive HGF/c-Met system. Together, these data suggest that AngIV analogs exert at least some of their biological activity through interference with the HGF/c-Met system and may have utility as therapeutic agents in disorders that are dependent on an intact HGF/c-Met system. Finally, the ability of norleual to induce marked biological responses in human embryonic kidney cells, which do not express insulin-responsive aminopeptidase (IRAP), coupled with the observed effects of norleual on the HGF/c-Met system, casts doubt on the physiological significance of AngIV-dependent inhibition of IRAP. |
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Authors:
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B J Yamamoto; P D Elias; J A Masino; B D Hudson; A T McCoy; Z J Anderson; M D Varnum; M F Sardinia; J W Wright; J W Harding |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-01-19 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 333 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-03-22 Completed Date: 2010-04-22 Revised Date: 2011-07-27 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 161-73 Citation Subset: IM |
Affiliation:
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Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Angiogenesis Inhibitors
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pharmacology Angiotensin II / analogs & derivatives*, chemistry Animals Cell Line Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Dogs Endothelial Cells / drug effects, physiology Endothelium, Vascular / cytology, drug effects Enzyme Activation Extracellular Signal-Regulated MAP Kinases / metabolism Hepatocyte Growth Factor / antagonists & inhibitors*, physiology Humans Lung / drug effects, pathology Lung Neoplasms / pathology Melanoma, Experimental / pathology Mice Mice, Inbred C57BL Oligopeptides / pharmacology* Proto-Oncogene Proteins c-met / antagonists & inhibitors*, physiology Radioligand Assay Signal Transduction |
| Grant Support | |
ID/Acronym/Agency:
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EY012836/EY/NEI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Angiogenesis Inhibitors; 0/Oligopeptides; 0/norleucyl-tyrosyl-leucyl-psi(CH2-NH2)(3-4)-histidyl-prolyl-phenylalanine; 11128-99-7/Angiotensin II; 23025-68-5/angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; 67256-21-7/Hepatocyte Growth Factor; EC 2.7.10.1/Proto-Oncogene Proteins c-met; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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