CD28 and Grb-2, relative to Gads or Grap, preferentially co-operate with Vav1 in the activation of NFAT/AP-1 transcription.
The co-receptor CD28 binds to several intracellular proteins including PI3 kinase, Grb-2, Gads and ITK. Grb-2 and PI3 kinase binding has been mapped to the pYMNM motif within the cytoplasmic tail of CD28 and has been shown to play a role in co-stimulation. In this study, we demonstrate that amongst the Grb-2 family adapter proteins, CD28 precipitated Grb-2 and specifically co-operated in the up-regulation of NFAT/AP-1 transcription. By contrast, Gads and Grap either failed or only weakly collaborated with CD28 ligation. Further, the loss of Grb-2 binding interferes with the ability of Vav1 to co-operate with CD28. Anti-CD28 ligation alone was capable for co-operating with Grb-2 or Grb-2-Vav1. Our findings define a pathway involving CD28 binding to Grb-2 and its co-operativity with Vav1 in the regulation of T-cell co-stimulation.
Schneider
Helga
H
Cell Signalling Section, Division of Immunology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Rudd
Christopher E
CE
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D050778:NFATC Transcription Factors / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C409587:GRAP2 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C510602:Grap protein, human; D050778:NFATC Transcription Factors; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human