Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase.
ZAP-70 and Syk are PTKs required for TCR and BCR function, respectively. Loss of the Syk PTK results in a nonfunctional BCR. We provide evidence here that ZAP-70 and Syk are functionally homologous in antigen receptor signaling by demonstrating that expression of ZAP-70 in Syk- B cells reconstitutes BCR function. Reconstitution required the presence of functional Src homology 2 (SH2) and catalytic domains of ZAP-70. Thus, drug targeting of a single SH2 domain within ZAP-70 should be sufficient to inhibit hematopoietic antigen receptor function. In addition, we demonstrate that both ZAP-70 and Syk can bind directly to the phosphorylated Ig alpha and Ig beta subunits with affinities comparable to their binding to the TCR CD3 epsilon subunit. These data suggest that ZAP-70 and Syk are comparable in their abilities to mediate hematopoietic antigen receptor signaling.
Kong
G H
GH
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Bu
J Y
JY
Kurosaki
T
T
Shaw
A S
AS
Chan
A C
AC
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D051925:CD79 Antigens; D002118:Calcium / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D015703:Antigens, CD; D017252:CD3 Complex; D051925:CD79 Antigens; C497881:CD79A protein, human; C497883:CD79B protein, human; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D002118:Calcium