A fusion of the EBV latent membrane protein-1 (LMP1) transmembrane domains to the CD40 cytoplasmic domain is similar to LMP1 in constitutive activation of epidermal growth factor receptor expression, nuclear factor-kappa B, and stress-activated protein kinase.
The EBV latent infection transforming protein, LMP1, has six hydrophobic transmembrane domains that enable it to aggregate in the plasma membrane and a 200-amino acid carboxyl-terminal cytoplasmic domain (CT) that activates nuclear factor-kappaB and induces many of the phenotypic changes in B lymphocytes that accompany CD40 activation. Since the phenotypic effects of LMP1 are similar to those of activated CD40, we now compare signaling from the LMP1 CT with that from the CD40 CT fused to the LMP1 transmembrane domains. The LMPCD40 chimera was similar to LMP1 in nuclear factor-kappaB activation and in up-regulation of epidermal growth factor receptor expression. CD40 ligation was known to activate the stress-activated protein kinase, and both LMPCD40 and LMP1 are now shown to induce stress-activated protein kinase activity in the absence of ligand. Deletion of the first four transmembrane domains of LMP1 abrogated LMP1 aggregation in the plasma membrane and nearly abolished signaling from LMP1 or the LMPCD40 chimera. These results highlight the role of LMP1 as a constitutively active receptor similar to CD40 and provide a novel approach for the generation of ligand-independent receptors.
Hatzivassiliou
E
E
Department of Microbiology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
Miller
W E
WE
Raab-Traub
N
N
Kieff
E
E
Mosialos
G
G
D019677:Artificial Gene Fusion; D019013:CD40 Antigens / Q000235:genetics* / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D066246:ErbB Receptors / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000276:immunology
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D008565:Membrane Proteins; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014763:Viral Matrix Proteins; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases