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

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BlankBlood First Edition Paper, prepublished online October 12, 2006; DOI

10.1182/blood-2006-03-011759.

Submitted March 21, 2006

Accepted October 10, 2006

ZAP-70 enhances B-cell receptor signaling in spite of absent or inefficient

tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B-cells

Stefania Gobessi, Luca ti, Pablo G Longo, Simona Sica, Giuseppe Leone, and

Dimitar G Efremov*

ICGEB Outstation - Monterotondo, CNR Campus " o Buzzati-Traverso " , Rome,

Italy

Hematology Institute, Universita Cattolica del Sacro Cuore, Rome, Italy

* Corresponding author; email: efremov@... .

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 was found to enhance and prolong activation of several key

mediators of BCR signaling, such as the Syk, ERK and Akt kinases, and to

decrease 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.