IG RECEPTOR-BINDING PROTEIN-1 (ALPHA-4) 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 im mune responses; however, its action in the signal transduction of lymp hocytes has remained largely unknown. We show here that a phosphoprote in encoded by mouse alpha 4 (m alpha 4) gene transmitting a signal thr ough B-cell antigen receptor (BCR) is associated with the catalytic su bunit of protein phosphatase 2A (PP2Ac). The middle region of a4, cons isting of 109 amino acids (94-202), associates directly with PP2Ac, ir respective of any other accessory molecule. Rapamycin treatment disrup ts the association of PP2Ac/alpha 4 in parallel with the inhibitory ef fect of lymphoid cell proliferation. The effect of rapamycin was inhib ited with an excess amount of FK506 that potentially completes the bin ding to FKBP. Rapamycin treatment also suppresses the phosphatase acti vity of cells measured by in vitro phosphatase assay. Introduction of the m alpha 4 cDNA into Jurkat cells or the increased association of P P2Ac/alpha 4 by the culture with low serum concentration confers cells with rapamycin resistance. Moreover, glutathione S-transferase (GST)- alpha 4 augments the PP2A activity upon myelin basic protein (MBP) and histone in the in vitro assay. These results suggest that alpha 4 act s as a positive regulator of PP2A and as a new target of rapamycin in the activation of lymphocytes. (C) 1998 by The American Society of Hem atology.