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Ig Receptor Binding Protein 1 ( 4) Is Associated With a
Rapamycin-Sensitive Signal Transduction in Lymphocytes Through Direct
Binding to the Catalytic Subunit of Protein Phosphatase 2A
Seiji Inui,
Hideki Sanjo,
Kazuhiko Maeda,
Hideyuki Yamamoto,
Eishichi Miyamoto, and
Nobuo Sakaguchi
From the Departments of Immunology and of Pharmacology, Kumamoto
University School of Medicine, Kumamoto, Japan.
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  4 (m4) 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 4,
consisting of 109 amino acids (94-202), associates directly with PP2Ac,
irrespective of any other accessory molecule. Rapamycin treatment
disrupts the association of PP2Ac/4 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 m4 cDNA into Jurkat cells or the increased association of
PP2Ac/4 by the culture with low serum concentration confers cells
with rapamycin resistance. Moreover, glutathione S-transferase
(GST)-4 augments the PP2A activity upon myelin basic protein (MBP)
and histone in the in vitro assay. These results suggest that 4 acts
as a positive regulator of PP2A and as a new target of rapamycin in the
activation of lymphocytes.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 539-546
© 1998 by the American Society of Hematology.
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