Ig receptor binding protein 1 (alpha4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2A.
Rapamycin is an immunosuppressant that effectively controls various immune responses; however, its action in the signal transduction of lymphocytes has remained largely unknown. We show here that a phosphoprotein encoded by mouse alpha4 (malpha4) gene transmitting a signal through B-cell antigen receptor (BCR) is associated with the catalytic subunit of protein phosphatase 2A (PP2Ac). The middle region of alph4, consisting of 109 amino acids (94-202), associates directly with PP2Ac, irrespective of any other accessory molecule. Rapamycin treatment disrupts the association of PP2Ac/alpha4 in parallel with the inhibitory effect of lymphoid cell proliferation. The effect of rapamycin was inhibited with an excess amount of FK506 that potentially completes the binding to FKBP. Rapamycin treatment also suppresses the phosphatase activity of cells measured by in vitro phosphatase assay. Introduction of the malpha4 cDNA into Jurkat cells or the increased association of PP2Ac/alpha4 by the culture with low serum concentration confers cells with rapamycin resistance. Moreover, glutathione S-transferase (GST)-alpha4 augments the PP2A activity upon myelin basic protein (MBP) and histone in the in vitro assay. These results suggest that alpha4 acts as a positive regulator of PP2A and as a new target of rapamycin in the activation of lymphocytes.
Inui
S
S
Department of Immunology, Kumamoto University School of Medicine, Kumamoto, Japan.
Sanjo
H
H
Maeda
K
K
Yamamoto
H
H
Miyamoto
E
E
Sakaguchi
N
N
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018832:Molecular Chaperones; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011090:Polyenes / Q000494:pharmacology*; D054648:Protein Phosphatase 2; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus
D048868:Adaptor Proteins, Signal Transducing; C490467:IGBP1 protein, human; C092377:Igbp1 protein, mouse; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D010750:Phosphoproteins; D011090:Polyenes; D011947:Receptors, Antigen, B-Cell; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D020123:Sirolimus