RGD Reference Report - The integrin alpha2beta1 agonist, aggretin, promotes proliferation and migration of VSMC through NF-kB translocation and PDGF production. - Rat Genome Database

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The integrin alpha2beta1 agonist, aggretin, promotes proliferation and migration of VSMC through NF-kB translocation and PDGF production.

Authors: Chung, CH  Lin, KT  Chang, CH  Peng, HC  Huang, TF 
Citation: Chung CH, etal., Br J Pharmacol. 2009 Mar;156(5):846-56. Epub 2009 Feb 23.
RGD ID: 2307394
Pubmed: PMID:19239475   (View Abstract at PubMed)
PMCID: PMC2697757   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1476-5381.2008.00095.x   (Journal Full-text)

BACKGROUND AND PURPOSE: During the development of atherosclerotic plaques, vascular smooth muscle cells (VSMCs) migrate from the media to the intima through the basement membrane and interstitial collagenous matrix, and proliferate to form neointima. Here, we investigate the mechanism of VSMC migration and proliferation caused by aggretin, a snake venom integrin alpha2beta1 agonist. EXPERIMENTAL APPROACH: Cultures of rat and human VSMCs were treated with aggretin and the signal transduction pathways induced by this agonist were examined by Western blotting, immunoprecipitation and electrophoretic mobility shift assay techniques. KEY RESULTS: Aggretin-induced VSMC proliferation was blocked by a monoclonal antibody (mAb) against integrin alpha2 (AII2E10) or against the platelet-derived growth factor receptor (PDGFR)-beta. Proliferation was also blocked by inhibition of the tyrosine kinase Src with PP2, phospholipase C (PLC) with U73122, extracellular signal-regulated kinase (ERK) with PD98059 or nuclear factor-kappa B (NF-kB) activation with pyrrolidine dithiocarbamate (PDTC). VSMC migration towards immobilized aggretin was increased in a modified Boyden chamber and this effect was blocked by alpha2beta1-Src-PLC-MAPK axis inhibitors, but not by PDTC, PDGFR-beta mAb, or a phosphoinositide-3 kinase inhibitor, LY294002. Aggretin stimulated the phosphorylation of PDGFR-beta, Src and ERK in a time-dependent manner. NF-kB translocation and platelet-derived growth factor (PDGF)-BB production were also observed. The ERK activation, NF-kB translocation and PDGF-BB production were blocked by PP2, U73122 and PD98059. CONCLUSIONS AND IMPLICATIONS: Aggretin induces VSMC proliferation and migration mainly through binding to integrin alpha2beta1, and subsequently activates Src, PLC and ERK pathways, inducing NF-kB activation and PDGF production.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of DNA binding  IMP 2307394DNA binding by NF-kappaBRGD 
positive regulation of smooth muscle cell migration  IMP 2307394 RGD 
positive regulation of smooth muscle cell proliferation  IMP 2307394 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Itga2  (integrin subunit alpha 2)


Additional Information