CAST, a novel CD3epsilon-binding protein transducing activation signal for interleukin-2 production in T cells.
Antigen recognition through T cell receptor (TCR)-CD3 complex transduces signals into T cells, which regulate activation, function, and differentiation of T cells. The TCR-CD3 complex is composed of two signaling modules represented by CD3zeta and CD3epsilon. Signaling through CD3zeta has been extensively analyzed, but that via CD3epsilon, which is also crucial in immature thymocyte development, is still not clearly understood. We isolated cDNA encoding a novel CD3epsilon-binding protein CAST. CAST specifically interacts in vivo and in vitro with CD3epsilon but not with CD3zeta or FcRgamma via a unique membrane-proximal region of CD3epsilon. CAST is composed of 512 amino acids including a single tyrosine and undergoes tyrosine phosphorylation upon TCR stimulation. Overexpression of two dominant-negative types of CAST, a minimum CD3epsilon-binding domain and a tyrosine-mutant, strongly suppressed NFAT activation and interleukin-2 production. These results demonstrate that CAST serves as a component of preformed TCR complex and transduces activation signals upon TCR stimulation and represents a new signaling pathway via the CD3epsilon-containing TCR signaling module.
Yamazaki
T
T
Department of Molecular Genetics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Hamano
Y
Y
Tashiro
H
H
Itoh
K
K
Nakano
H
H
Miyatake
S
S
Saito
T
T
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017252:CD3 Complex; D002352:Carrier Proteins / Q000737:chemistry* / Q000502:physiology*; D018076:DNA, Complementary / Q000737:chemistry; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D012318:RNA Polymerase I; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D017252:CD3 Complex; C115335:CD3E protein, human; D002352:Carrier Proteins; D018076:DNA, Complementary; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; C119975:POLR1G protein, human; D012318:RNA Polymerase I