ZAP-70 enhances B-cell receptor signaling in spite of absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B-cells

Authors:
Gobessi S, Laurenti L, Longo PG, Sica S, Leone G, Efremov DG
In:
Source: Blood
Publication Date: (2007)
Issue: 109(5): 2032-9
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
BJAB
Species: human
Tissue Origin: blood
Jurkat
Species: human
Tissue Origin: blood
B-CLL
Species: human
Tissue Origin: blood
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
Expression of ZAP-70 is an important negative prognostic factor in chronic lymphocytic leukemia (CLL). This protein tyrosine kinase is a key mediator of T-cell receptor (TCR) signaling and is structurally homologous to Syk, which plays an analogous role in B-cell receptor (BCR) signaling. Recent studies indicate that ZAP-70 may participate in BCR signaling as well, but the mechanism of action is not completely understood. We have now compared antigen receptor-induced activation of ZAP-70 in B cells and T cells by analyzing phosphorylation of critical regulatory tyrosine residues. We show that BCR-mediated activation of ZAP-70 is very inefficient in CLL and lymphoma B cells and is negligible when compared to activation of Syk. Despite the inefficient catalytic activation, the ability of ZAP-70 to recruit downstream signaling molecules in response to antigen receptor stimulation appeared relatively preserved. Moreover, ectopic expression of ZAP-70 enhanced and prolonged activation of several key mediators of BCR signaling, such as the Syk, ERK, and Akt kinases, and decreased the rate of ligand-mediated BCR internalization. We conclude that the role of ZAP-70 in BCR signaling is quite distinct from its role in TCR signaling and is likely mediated by inhibition of events that terminate the signaling response.