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 Laurenti, Pablo G Longo, Simona Sica, Giuseppe Leone, and Dimitar G Efremov*
ICGEB Outstation - Monterotondo, CNR Campus "Adriano Buzzati-Traverso", Rome, Italy
Hematology Institute, Universita Cattolica del Sacro Cuore, Rome, Italy
* Corresponding author; email: efremov{at}icgeb.org.
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.
