Document Detail


Ephrin-B3 ligand promotes glioma invasion through activation of Rac1.
MedLine Citation:
PMID:  16951161     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Eph receptor tyrosine kinases are involved in nervous system development. Eph ligands, termed ephrins, are transmembrane proteins that bind to Eph receptors, the mutual activation of which causes repulsive effects in reciprocally contacting cells. Previously, we showed that overexpression of EphB2 in glioma cells increases cell invasion. Here, expression profiles of ephrin-B family members were determined in four glioma cell lines and in invading glioblastoma cells collected by laser capture microdissection. Ephrin-B3 mRNA was up-regulated in migrating cells of four of four glioma cell lines (1.3- to 1.7-fold) and in invading tumor cells of eight of eight biopsy specimens (1.2- to 10.0-fold). Forced expression of ephrin-B3 in low expressor cell lines (U87, T98G) stimulated cell migration and invasion in vitro and ex vivo, concomitant with tyrosine phosphorylation of ephrin-B3. In high expressor cell lines (U251, SNB19), ephrin-B3 colocalized with Rac1 to lamellipodia of motile wild-type cells. Cells transfected with ephrin-B3 small interfering RNA (siRNA) showed significant morphologic change and decreased invasion in vitro and ex vivo. Depletion of endogenous ephrin-B3 expression abrogated the increase of migration and invasion induced by EphB2/Fc, indicating increased invasion is dependent on ephrin-B3 activation. Furthermore, using a Rac1-GTP pull-down assay, we showed that ephrin-B3 is associated with Rac1 activation. Reduction of Rac1 by siRNA negated the increased invasion by addition of EphB2/Fc. In human glioma specimens, ephrin-B3 expression and phosphorylation correlated with increasing tumor grade. Immunohistochemistry revealed robust staining for phosphorylated ephrin-B and ephrin-B3 in invading glioblastoma cells. These data show that ephrin-B3 expression and signaling through Rac1 are critically important to glioma invasion.
Authors:
Mitsutoshi Nakada; Kelsey L Drake; Satoko Nakada; Jared A Niska; Michael E Berens
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-09-04     Completed Date:  2007-11-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8492-500     Citation Subset:  IM    
Affiliation:
The Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Astrocytoma
Brain / pathology
Cell Line, Tumor
Cell Movement
DNA Primers
Ephrin-B3 / genetics,  physiology*
Gene Expression Regulation, Neoplastic
Glioma / pathology*,  physiopathology
Humans
Immunohistochemistry
Ligands
Neoplasm Invasiveness
Phosphorylation
Plasmids
RNA, Small Interfering / genetics
Rats
Reverse Transcriptase Polymerase Chain Reaction
Transfection
Transplantation, Heterologous
rac1 GTP-Binding Protein / metabolism*
Grant Support
ID/Acronym/Agency:
NS042262/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Ephrin-B3; 0/Ligands; 0/RNA, Small Interfering; EC 3.6.5.2/rac1 GTP-Binding Protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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