Abstract
Bruton's tyrosine kinase (BTK) regulates the B-cell receptor (BCR) signaling pathway, which, in turn, plays a critical role in B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis. The BTK-specific inhibitor Ibrutinib blocks BCR signaling and is now approved as effective B-CLL therapy. Chemokines, such as the homeostatic chemokine CXCL12, play a central role in B-CLL pathogenesis and progression, by regulating CLL cell interaction with the stromal microenvironment, leading to cells survival and proliferation. In this study, we investigated, in normal versus CLL B-lymphocytes, the role of BTK in signal transduction activated by the CXCL12-CXCR4 signaling axis and its involvement in rapid integrin activation. We show that BTK is rapidly activated by CXCL12 in healthy as well as CLL B-lymphocytes, with a kinetic of tyr-phosphorylation coherent with rapid adhesion triggering. BTK inhibition prevents CXCL12-induced triggering of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) integrins. Furthermore, BTK inhibition blocks the activation of the small GTP-binding protein RhoA, controlling integrin affinity. Very importantly, we show that BTK tyr-phosphorylation and activation by CXCL12 depends on upstream activation of JAK2 tyrosine kinase. A comparative analysis of 36 B-CLL patients demonstrates that JAK2-dependent BTK regulatory role on integrin activation by CXCL12 is fully conserved in CLL cells. Finally, we show that the JAK2-BTK axis also regulates signaling to integrin activation by BCR. Thus, BTK and JAK protein tyrosine kinases (PTKs) manifest a hierarchical activity both in chemokine- as well as BCR-mediated integrin activation and dependent adhesion, potentially suggesting the possibility of combined therapeutic approaches to B-CLL treatment.
Highlights
Integrin-mediated adhesion is a central regulatory process in cell biology, including development, immune system regulation and cancer
We found that Bruton’s tyrosine kinase (BTK) was rapidly phosphorylated on Y223 by C-X-C motif chemokine 12 (CXCL12), with kinetics consistent with rapid adhesion triggering (Figure 1A and 1C)
In previous studies we investigated the role of the rho module of integrin affinity triggering and of JAK protein tyrosine kinases (PTKs) in integrin activation by CXCL12 in B-cell chronic lymphocytic leukemia (B-CLL) [25]
Summary
Integrin-mediated adhesion is a central regulatory process in cell biology, including development, immune system regulation and cancer. Chemokines, and more in general chemoattractants, are the most potent integrin activators, and regulate integrin-mediated leukocyte adhesion by www.oncotarget.com triggering a cascade of intracellular signaling events, involving at least 70 different signaling molecules [2]. This very complex signaling mechanism leads to very rapid integrin affinity maturation and valency upregulation, altogether mediating increased leukocyte adhesiveness. In such a complexity, where concurrency and stochasticity emerge as natural outcomes [3], anomalies related to cancer progression may potentially occur [4,5,6,7,8,9]
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