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Division of Tumor Immunology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115; and
Department of Clinical Immunology and AIDS Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
ß1 integrins provide a costimulus for TCR/CD3-driven
T cell activation and IL-2 production in human peripheral T cells.
However, this ß1 integrin-mediated costimulation is
impaired in a human T lymphoblastic line, Jurkat. We studied the
molecular basis of this impaired costimulation and found that Cas-L, a
105-kDa docking protein, is marginally expressed in Jurkat T cells,
whereas Cas-L is well expressed in peripheral T cells. Cas-L is a
binding protein and a substrate for focal adhesion kinase and is
tyrosine phosphorylated by ß1 integrin stimulation. We
here show that the transfection of wild-type Cas-L in Jurkat T cells
restores ß1 integrin-mediated costimulation. However,
Cas-L transfection had no effect on CD28-mediated costimulation,
indicating that Cas-L is specifically involved in the ß1
integrin-mediated signaling pathway. Furthermore, transfection of the
Cas-L
SH3 mutant failed to restore ß1 integrin-mediated
costimulation in Jurkat cells. Cas-L
SH3 mutant lacks the binding
site for focal adhesion kinase and is not tyrosine phosphorylated after
ß1 integrin stimulation. These findings strongly suggest
that the tyrosine phosphorylation of Cas-L plays a key role in the
signal transduction in the ß1 integrin-mediated T cell
costimulation.
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