RGD Reference Report - EphA4-mediated Rho activation via Vsm-RhoGEF expressed specifically in vascular smooth muscle cells. - Rat Genome Database

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EphA4-mediated Rho activation via Vsm-RhoGEF expressed specifically in vascular smooth muscle cells.

Authors: Ogita, H  Kunimoto, S  Kamioka, Y  Sawa, H  Masuda, M  Mochizuki, N 
Citation: Ogita H, etal., Circ Res. 2003 Jul 11;93(1):23-31. Epub 2003 May 29.
RGD ID: 8554375
Pubmed: PMID:12775584   (View Abstract at PubMed)
DOI: DOI:10.1161/01.RES.0000079310.81429.C8   (Journal Full-text)

Rho-kinase, an effector of Rho GTPase, increases the contractility of vascular smooth muscle by phosphorylating myosin light chain (MLC) and by inactivating MLC phosphatase. A wide variety of extracellular stimuli activate RhoA via G protein-coupled receptors. In the present study, we demonstrate a novel cell-cell interaction-mediated Rho activation signaling pathway in vascular smooth muscle cells (VSMCs). Among many receptor tyrosine kinases, the Eph family receptors are unique in that they require cell-cell interaction to engage their ligands, ephrin. We found that a novel VSMC-specific guanine nucleotide exchange factor (GEF) for Rho (Vsm-RhoGEF/KIAA0915) was expressed specifically in VSMCs of several organs including the heart, aorta, liver, kidney, and spleen, as examined by the immunohistochemical analysis using a specific antibody against Vsm-RhoGEF. Based on the association of Vsm-RhoGEF with EphA4 in quiescent cells, we tested whether EphA4 and Vsm-RhoGEF were expressed in the same tissue and further studied the molecular mechanism of Vsm-RhoGEF regulation by EphA4. Immunohistochemical analysis showed that EphA4 and Vsm-RhoGEF expression overlapped in VSMCs. Additionally, tyrosine phosphorylation of Vsm-RhoGEF induced by EphA4 upon ephrin-A1 stimulation enhanced the Vsm-RhoGEF activity for RhoA. The requirement of Vsm-RhoGEF for ephrin-A1-induced assembly of actin stress fibers in VSMCs was shown by the overexpression of a dominant-negative form of VSM-RhoGEF and by the depletion of Vsm-RhoGEF using RNA interference. These results suggested that ephrin-A1-triggered EphA4-Vsm-RhoGEF-RhoA pathway is involved in the cell-cell interaction-mediated RhoA activation that regulates vascular smooth muscle contractility.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Arhgef15Ratpositive regulation of stress fiber assembly involved_inIDA PMID:12775584UniProt 
Arhgef15Ratregulation of catalytic activity involved_inIDA PMID:12775584UniProt 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Arhgef15Ratcytoplasm located_inIDA PMID:12775584UniProt 
Epha4Ratcytoplasm located_inIDA PMID:12775584UniProt 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Arhgef15Ratguanyl-nucleotide exchange factor activity enablesIDA PMID:12775584UniProt 
Arhgef15Ratprotein binding enablesIPIUniProtKB:D3ZZK3PMID:12775584UniProt 
Epha4Ratprotein binding enablesIPIUniProtKB:A0A0G2JTU0PMID:12775584UniProt 
Epha4Ratprotein binding enablesIPIUniProtKB:D3ZPJ8PMID:12775584UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Arhgef15  (Rho guanine nucleotide exchange factor 15)
Epha4  (Eph receptor A4)


Additional Information