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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2032-2039.
Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-03-011759.
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IMMUNOBIOLOGY
ZAP-70 enhances B-cell–receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells
Stefania Gobessi1,
Luca Laurenti2,
Pablo G. Longo1,
Simona Sica2,
Giuseppe Leone2, and
Dimitar G. Efremov1
1 International Centre for Genetic Engineering and Biotechnology (ICGEB) Outstation-Monterotondo, Consiglio Nazionale delle Ricerche (CNR) Campus "Adriano Buzzati-Traverso," Rome, Italy;
2 Hematology Institute, Università Cattolica del Sacro Cuore, Rome, Italy
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.
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