Activation of Epstein-Barr virus/C3d receptor (gp140, CR2, CD21) on human cell surface triggers pp60src and Akt-GSK3 activities upstream and downstream to PI 3-kinase, respectively.
We previously demonstrated that CR2 activation on human B lymphocyte surface specifically triggered tyrosine phosphorylation of the 95-kDa nucleolin, this leading to its binding on SH2 domains of p85 sub-unit of PI 3-kinase and to activation of this enzyme. The specificity of CR2 pathway was clearly demonstrated as neither CD19 nor BCR could induce tyrosine phosphorylation of nucleolin in normal B lymphocytes. These data led us to investigate herein additional molecular events, which were triggered by CR2 activation, upstream and downstream to PI 3-kinase activation. Upstream, we demonstrated that pp60src, a tyrosine kinase of the src family, was involved in tyrosine phosphorylation of nucleolin, while syk tyrosine kinase was not. We also demonstrated a direct protein-protein interaction of pp60src with nucleolin in a CR2-dependent and CD19-independent pathway. Downstream, we demonstrated that CR2 activation also triggered Akt and GSK3 enzyme activation, this pathway being under the control of pp60src tyrosine kinase activation. These regulatory functions of activated CR2 were specific as independent of syk tyrosine kinase and of CD19 and BCR activation. Thus, CR2 activation recruits a specific mechanism to activate PI 3-kinase and its subsequent pathways, this mechanism being different to those recruited by CD19 and BCR.
Barel
Monique
M
Immunochimie des Régulations Cellulaires et des Interactions Virales, INSERM U.354, Evry, France. barel354@genopole.evry.inserm.fr
Balbo
Michelle
M
Le Romancer
Muriel
M
Frade
Raymond
R
D018941:Antigens, CD19 / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000378:metabolism*; D000097796:Nucleolin
D018941:Antigens, CD19; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src); D016601:RNA-Binding Proteins; D017464:Receptors, Complement 3d; D000097796:Nucleolin; C494918:AKT1 protein, human