F2(Pmp)2-TAM zeta 3, a novel competitive inhibitor of the binding of ZAP-70 to the T cell antigen receptor, blocks early T cell signaling.
Signaling by the T cell antigen receptor (TCR) is mediated by 17-residue tyrosine-based activation motifs (TAM) present in the cytoplasmic tails of the TCR zeta and CD3 chains. TAMs become tyrosine-phosphorylated upon TCR stimulation, creating a high affinity binding site for the tandem SH2 domains of ZAP-70. In permeabilized T cells, the association of TCR and ZAP-70 was inhibited by a protein tyrosine phosphatase (PTPase)-resistant TAM peptide analog, in which difluorophosphonomethyl phenylalanyl (F2Pmp) residues replaced phosphotyrosine. Inhibition of this association prevented TCR-stimulated tyrosine phosphorylation of ZAP-70 and reduced ZAP-70 kinase activity to basal levels. The reduction in ZAP-70 activity coincided with reduced tyrosine phosphorylation of a number of substrates. Such PTPase-resistant peptides, capable of disrupting SH2 domain-mediated protein-protein interactions, should prove useful in further dissection of multiple signaling pathways and may serve as models for rationally designed chemotherapeutic agents for the treatment of autoimmune and neoplastic disorders.
Wange
R L
RL
Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
Isakov
N
N
Burke
T R
TR
Otaka
A
A
Roller
P P
PP
Watts
J D
JD
Aebersold
R
R
Samelson
L E
LE
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
C091467:F2(Pmp)2-TAMzeta3 peptide; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human