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J Biol Chem, Vol. 273, Issue 31, 19914-19921, July 31, 1998
From the Human CD2 is a 50-55-kDa cell surface receptor
specifically expressed on the surface of T lymphocytes and NK cells.
Stimulation of human peripheral blood T cells with mitogenic pairs of
anti-CD2 monoclonal antibodies (mAbs) is sufficient to induce
interleukin-2 production and T cell proliferation in the absence of an
antigen-specific signal through the T cell receptor. CD2 has been shown
previously to associate physically with the Src family protein-tyrosine
kinases p56lck and p59fyn. We now report that
stimulation of T cells with mitogenic pairs of anti-CD2 mAbs enhanced
the association of the Fyn polypeptide with the CD2 complex, whereas
stimulation with single anti-CD2 mAb had minimal effect. Using
glutathione S-transferase (GST) fusion proteins, we found
that CD2 bound to the Src homology (SH) 3 domain of Fyn. Interestingly,
the CD2-Fyn association was negatively regulated by the Fyn SH2 domain;
CD2 bound poorly to GST fusion proteins expressing both the SH2 and SH3
domains of Fyn. However, the inhibitory effect of the Fyn SH2 domain on
binding of the Fyn SH3 domain to CD2 was relieved by peptides
containing a phosphorylated YEEI sequence that bound directly to the
Fyn SH2 domain. In addition, we found that the ability of the Fyn SH2
domain to precipitate tyrosine-phosphorylated proteins, including the
CD3
Association of p59fyn with the T Lymphocyte
Costimulatory Receptor CD2
BINDING OF THE Fyn Src HOMOLOGY (SH) 3 DOMAIN IS REGULATED BY
THE Fyn SH2 DOMAIN
§,,
,**
Department of Pediatric Oncology,
Dana-Farber Cancer Institute, § Committee on Immunology, Department of
Pathology and Laboratory Medicine, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104, and the ** Department of
Medicine, Harvard Medical School, Boston, Massachusetts 02115
chain, was enhanced after T cell stimulation with mitogenic
pairs of CD2 mAbs. Finally, overexpression of a mutated Fyn
molecule, in which the ability of the Fyn SH2 domain to bind
phosphotyrosine-containing proteins was abrogated, inhibited
CD2-induced transcriptional activation of the nuclear factor of
activated T cells (NFAT), suggesting a functional involvement of the
Fyn SH2 domain in CD2-induced T cell signaling. We thus propose that
stimulation through the CD2 receptor leads to the tyrosine
phosphorylation of intracellular proteins, including CD3 itself,
which in turn bind to the Fyn-SH2 domain, allowing the direct
association of the Fyn SH3 domain with CD2 and the initiation of
downstream signaling events.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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