Ig Receptor Binding Protein 1 (α4) Is Associated With a Rapamycin-Sensitive Signal Transduction in Lymphocytes Through Direct Binding to the Catalytic Subunit of Protein Phosphatase 2A

Abstract

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 α4 (mα4) 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 α4, consisting of 109 amino acids (94-202), associates directly with PP2Ac, irrespective of any other accessory molecule. Rapamycin treatment disrupts the association of PP2Ac/α4 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 mα4 cDNA into Jurkat cells or the increased association of PP2Ac/α4 by the culture with low serum concentration confers cells with rapamycin resistance. Moreover, glutathione S-transferase (GST)-α4 augments the PP2A activity upon myelin basic protein (MBP) and histone in the in vitro assay. These results suggest that α4 acts as a positive regulator of PP2A and as a new target of rapamycin in the activation of lymphocytes.